Translational control is one of primary regulation mechanisms of gene expression. Eukaryotic translational control mainly occurs at the initiation step, the speed-limiting step, which involves more than ten translation initiation factors [eIFs (eukaryotic initiation factors)]. Changing the level or function of these eIFs results in abnormal translation of specific mRNAs and consequently abnormal growth of cells that leads to human diseases, including cancer. Accumulating evidence from recent studies showed that the expression of many eIFs was associated with malignant transformation, cancer prognosis, as well as gene expression regulation. In the present paper, we perform a critical review of recent advances in understanding the role and mechanism of eIF action in translational control and cancer as well as the possibility of targeting eIFs for therapeutic development.

INTRODUCTION

The gene expression process is complicated but accurately controlled by multiple levels of regulation. The two primary mechanisms of regulation of gene expression are transcription to convert genetic codes from DNA into mRNAs and translation of mRNAs to produce proteins. Deregulation at any one of these steps results in abnormal gene expression and thus uncontrolled cell growth and possibly human diseases, including cancer. In eukaryotes, mRNA translation consists of three major steps: initiation, elongation and termination. The translational regulation mainly occurs at initiation, the rate-limiting step, which involves at least 11 translation initiation factors [eIFs (eukaryotic initiation factors)] with some as multi-subunit complexes [1].

Previous studies and the accumulating evidence showed that the expression of many eIFs was associated with malignant transformation, cancer prognosis, as well as gene expression regulation [2,3]. In the present review, we focus on the recent advances in understanding the role and mechanism of eIF action in translational regulation, cell proliferation and cancer as well as the possibility of targeting eIFs for therapeutic development.

OVERVIEW OF INITIATION OF mRNA TRANSLATION

Translational initiation in eukaryotes is a complex event (Figure 1) that involves more than 25 molecules [1] and consists of four steps: (i) binding of the ternary complex composed of eIF2, Met-tRNAi (initiator methionyl-tRNA) and GTP to the 40S ribosomal subunit to form the 43S pre-initiation complex; (ii) introducing the complex of mRNA, eIF4B and eIF4F to the 43S pre-initiation complex; (iii) scanning along mRNA to the AUG start codon and forming the 48S pre-initiation complex; and (iv) binding of the 60S ribosomal subunit to 48S pre-initiation complex and forming the 80S ribosome for elongation while releasing initiation factors.

Schematic model of translation initiation in eukaryotes

Figure 1
Schematic model of translation initiation in eukaryotes

Initiation factors and ribosomes are shown as self-explanatory symbols. The 43S and 48S pre-initiation complexes, the 80S initiation complex, the 5′-cap structure (m7G), the initiation codon (AUG), and the 3′-poly(A) tail of an mRNA are also indicated and self-explanatory.

Figure 1
Schematic model of translation initiation in eukaryotes

Initiation factors and ribosomes are shown as self-explanatory symbols. The 43S and 48S pre-initiation complexes, the 80S initiation complex, the 5′-cap structure (m7G), the initiation codon (AUG), and the 3′-poly(A) tail of an mRNA are also indicated and self-explanatory.

As shown in Figure 1, the formation of the ternary complex consisting of eIF2, GTP and tRNAMet (methionine tRNA) is a prerequisite for the translational initiation. This ternary complex then binds to the 40S ribosomal subunit associated with eIF1, 1A, 3 and 5 to form the 43S pre-initiation complex. The 5′ m7GpppN cap structure of mRNAs, meanwhile, recruits and binds to eIF4E in the eIF4F trimeric complex consisting of eIF4A, eIF4E and eIF4G. While eIF4E functions to recognize and bind to the 5′-cap structure of mRNAs, eIF4A is an ATP-dependent DEAD box RNA helicase to facilitate unwinding of secondary structures of mRNAs and eIF4G functions as a scaffold protein bridging eIF4A and eIF4E. Interaction between eIF4G and eIF3 helps recruit the 43S pre-initiation complex to mRNA to form the 48S pre-initiation complex. Furthermore, eIF4G also interacts with PABP [poly(A)-binding protein] at the 3′ poly(A) tail of mRNAs, contributing to the recruitment of the 43S pre-initiation complex to the mRNA.

Following the binding of both 43S pre-initiation complex and eIF4F trimeric complex to mRNAs, the ribosome scans downstream along the mRNA until it identifies and interacts stably with the AUG initiation codon. This process consumes energy from ATP hydrolysis and contributes to the formation of the 48S initiation complex. During the scanning, eIF1 and eIF1A facilitate the localization of ribosome to the initiation codon. Subsequently, GTP in the eIF2–Met-tRNAi–GTP ternary complex along with the GTP in eIF5B are hydrolysed to provide energy for the 60S ribosome subunit to associate with the initiation complex, followed by release of the initiation factors and formation of the 80S ribosome to complete the initiation steps for cap-dependent translation.

eIFs AND CANCER

The accumulating evidence suggests that eIFs may be a new group of proto-oncogenes or tumour suppressors [2,3]. The altered expression of eIFs has been found in a wide range of tumours (Table 1). In some cases, the altered expression of eIFs also correlates with prognosis of cancer patients. In the following, we will highlight recent findings on eIF expression in association with human cancers.

Table 1
Altered expression of eIFs in human cancers
eIFExpression in human cancersReference(s)
eIF2α ↑ in lymphoma, stomach, colon, lung and thyroid cancers [611
eIF3a ↑ in breast, cervix, oesophagus, gastric and lung cancers [1519
eIF3c ↑ in testicular cancers, ↓ in melanoma [23,24
eIF3e ↓ in breast, colon and lung cancers [3134
eIF3f ↓ in melanoma and pancreas cancers [3537
eIF3h ↑ in breast, prostate, liver and lung cancers [3944
eIF3i ↑ in head and neck, liver and cadmium-induced cancers [5255
eIF4AI ↑ in melanoma and liver cancers [59,60
eIF4E ↑ in larynx, breast, cervix, colon, oesophagus, stomach, lymphoma, leukaemia, prostate, skin, lung, neck and head cancers [7,12,6178
eIF4G-1 ↑ in lung, prostate, cervical, breast, head and neck cancers [9499
eIF4G-2 ↓ in bladder cancers [104
eIF6 ↑ in colon, ovary, leukaemia, head and neck cancers [112,147149
eIFExpression in human cancersReference(s)
eIF2α ↑ in lymphoma, stomach, colon, lung and thyroid cancers [611
eIF3a ↑ in breast, cervix, oesophagus, gastric and lung cancers [1519
eIF3c ↑ in testicular cancers, ↓ in melanoma [23,24
eIF3e ↓ in breast, colon and lung cancers [3134
eIF3f ↓ in melanoma and pancreas cancers [3537
eIF3h ↑ in breast, prostate, liver and lung cancers [3944
eIF3i ↑ in head and neck, liver and cadmium-induced cancers [5255
eIF4AI ↑ in melanoma and liver cancers [59,60
eIF4E ↑ in larynx, breast, cervix, colon, oesophagus, stomach, lymphoma, leukaemia, prostate, skin, lung, neck and head cancers [7,12,6178
eIF4G-1 ↑ in lung, prostate, cervical, breast, head and neck cancers [9499
eIF4G-2 ↓ in bladder cancers [104
eIF6 ↑ in colon, ovary, leukaemia, head and neck cancers [112,147149

eIF2

eIF2, consisting of α, β and γ subunits, is a component of the eIF2–Met-tRNAi–GTP ternary complex and has activity to hydrolyse GTP. Exchange of the hydrolysed GDP by GTP is catalysed by eIF2B, which consists of five non-identical subunits. The process of GTP binding to eIF2 is one of the major rate-limiting contributors to the initiation step of mRNA translation. The α-subunit (eIF2α) is the regulatory subunit and small changes in its phosphorylation status at Ser51 causes dramatic effects on protein synthesis [4]. The first study that links eIF2 to tumorigenesis was the observation that abrogation of eIF2α phosphorylation by mutating the Ser51 residue to an alanine residue or by introducing a PKR (double-stranded-RNA-dependent protein kinase) that inhibits eIF2α phosphorylation promoted malignant cell transformation of NIH 3T3 cells [5]. These findings suggest that eIF2 may play a role in tumorigenesis and regulate cell proliferation.

Indeed, the altered expression level of eIF2α has been found in tumour cells or tissues compared with their normal counterparts. For example, using immunohistochemistry to study the expression of eIF2α in reactive lymph nodes and non-Hodgkin's lymphoma, Wang et al. [6] found high eIF2α levels in the germinal centres of reactive follicles and lymphocytes, but minimal or no expression in the mantle zone or surrounding paracortices [6]. Furthermore, elevated eIF2α expression was found in both classical and lymphocyte-predominant Hodgkin's lymphoma [7], gastrointestinal [8], bronchioloalveolar [9] and conventional papillary and aggressive thyroid [10] carcinomas. In addition, the increased expression of eIF2α was also found in both benign and malignant neoplasms of melanocytes [11]. Clearly, the increased expression of eIF2α correlates with different types of cancers, and elevating the expression level of eIF2α may be the cause of these cancers.

However, in other studies, it was also found that the expression level of eIF2α was not changed in cancers such as astrocytic and oligodendroglial tumours as well as meningiomas [12] and lung squamous cell carcinoma [9]. These different findings indicate that the role of eIF2α in tumorigenesis may be more complicated and it is possible that the role of eIF2α in translational regulation and cell growth control may differ in different tissues or cell types. Nevertheless, all these studies appeared to miss one important aspect of eIF2α, namely the phosphorylation status. Based on the studies with cell lines and xenograft models, it was thought that the unphosphorylated eIF2α is oncogenic [5]. Thus more studies are needed to further investigate whether the level of phosphorylated eIF2α is reduced in human tumours and if eIF2α regulates translation.

eIF3

eIF3 is the largest and most complex initiation factor with a molecular mass of 600–700 kDa in mammalian cells containing multiple subunits [13]. At least 13 putative subunits of eIF3 have been identified and were named as eIF3a–eIF3m [2,14]. A growing body of findings suggest that many of the eIF3 subunits may play important roles in translational regulation and tumorigenesis in addition to their putative housekeeping functions [2].

eIF3a

The largest subunit of the eIF3 complex, has been found with overexpression in several human cancers, including breast [15], cervix [16], oesophagus [17], stomach [18], lung [19] and colon (Z. Dong, J. Liu and J. T. Zhang, unpublished work). The increased eIF3a expression was more frequently observed at the early invasive stage of tumours [1618]. Thus alteration of eIF3a expression may be the early event of tumorigenesis. Indeed, knocking down eIF3a expression reversed the malignant phenotype of human lung and breast cancer cell lines [20]. Compared with control cells, the cells with stable eIF3a knockdown had lower colony formation efficiency, lower proliferation rate and smaller colony sizes. It has also been shown that overexpression of ectopic eIF3a led to malignant transformation of NIH 3T3 cells [21]. Thus eIF3a may play a critical role in tumorigenesis and in maintaining the malignant phenotype of cancer cells.

In a recent study, Olson et al. [22] screened variants of 30 genes in 798 breast cancer patients and 843 controls and found two eIF3a variants [SNPs (single nucleotide polymorphisms), rs10787899 and rs3824830] that were significantly associated with breast cancer risk. Compared with wild-type eIF3a, these two homozygote eIF3a variants had a 50% increase in risk of breast cancers. While the rs10787899 variation occurs in intron 19, the rs3824830 variation is located in the 5′-UTR (5′-untranslated region). Whether these variations affect eIF3a expression, which in turn increases breast cancer risk, requires further investigation.

eIF3c

eIF3c is a 110 kDa subunit of eIF3 and its gene is located at 16p11.2. Using differential display in combination with in situ hybridization and real-time PCR to compare gene expression between 25 testicular seminomas and seven normal testicular biopsies, Rothe et al. [23] found that eIF3c expression was up-regulated in testicular seminomas. In another study to compare gene expression in cell lines derived from a primary melanoma and its metastatic supraclavicular lymph node of the same patient using cDNA array, Baldi et al. [24] identified eIF3c as one of the 26 genes that were up-regulated in the metastatic cancer cells. The up-regulated eIF3c expression in metastatic melanoma cells was also confirmed using Northern blotting. However, these two studies are only correlative and none have gone into more in-depth analyses of the possible role of eIF3c in tumorigenesis/metastasis and the mechanism therein.

In a more recent study of meningiomas, eIF3c was found to interact with a tumour suppressor protein, schwannomin or merlin [25]. Tumours that have lost schwannomin have high levels of eIF3c and vice versa. The proliferation-suppression function of schwannomin appears to be dependent on eIF3c, and schwannomin was most effective in inhibiting cellular proliferation when eIF3c was highly expressed. These observations suggest that the tumour suppressor function of schwannomin may work by interacting with and inhibiting eIF3c, which may promote proliferation and tumorigenesis in the absence of schwannomin. It is noteworthy that the eIF3c gene is located in a region of chromosome 16 that is unstable and frequently involved in gene amplification [26]. Sequencing of human chromosome DNA has revealed that the entire coding region of eIF3c is duplicated. In cancer cells, the eIF3c gene may be amplified and this amplification may be the cause of increased eIF3c expression in cancers.

eIF3e

The gene encoding eIF3e/Int6 was first identified as a common integration site for MMTV (murine-mammary-tumour virus) in mammary alveolar epithelial cells [27]. MMTV insertion results in expression of a C-terminally truncated eIF3e protein, which was believed to be the cause of mammary tumorigenesis. Indeed, overexpression of the truncated eIF3e protein in MCF10A, HC11, NIH 3T3 and alveolar epithelial cells led to malignant transformation, whereas expression of the full-length wild-type eIF3e did not [2830]. Mammary-specific expression of the truncated eIF3e in mammary alveolar epithelial cells of transgenic mice induced tumour formation in approx. 42% of the animals at an average of 18 months of age compared with 4% of control mice that developed tumours in 2 years [29]. Thus the truncated eIF3e may act as an oncoprotein, while the wild-type full-length eIF3e does not. Interestingly, it has also been found that wild-type eIF3e expression was decreased in human cancers, including cancers of breast [31,32], colon [33] and lung [34]. Whether the wild-type full-length eIF3e functions as a tumour suppressor and its truncation only knocked out its tumour suppressor function is currently unknown and awaits further investigations.

eIF3f

Similar to eIF3e (Table 1), eIF3f has also been consistently observed to have decreased expression in human cancers including melanoma and pancreatic cancers [3537]. For example, there was a prevalent LOH (loss of heterozygosity) in pancreatic cancer tissues and the gene copy number of eIF3f was reduced in the pancreatic cancer tissues compared with the normal ones [37]. Overexpressing eIF3f inhibited proliferation and induced apoptosis in both pancreatic cancer and melanoma cell lines, whereas down-regulating its expression attenuated apoptosis [36]. Furthermore, eIF3f overexpression inhibited global protein synthesis by reducing the number of ribosomes, possibly due to rRNA degradation. However, how eIF3f overexpression causes rRNA degradation remains to be determined. Nevertheless, it is possible that eIF3f, similar to eIF3e, has tumour suppressor function by suppressing translation of mRNAs encoding oncogenic proteins. However, further studies are clearly needed to test this possibility.

eIF3h

eIF3h is another subunit of the eIF3 complex that may have positive correlation with tumorigenesis. The gene encoding eIF3h is located on chromosome 8 (8q23-q24) and amplification of this region has been reported in many solid tumours, including cancers of breast [3840], prostate [3842], liver [43] and lung [44]. The increased expression of eIF3h has also been found in primary breast cancers [40] and advanced stage and hormone-refractory prostate cancers [39]. Enforced expression of ectopic eIF3h led to malignant transformation of NIH 3T3 cells, attenuated apoptosis and enhanced translation of mRNAs encoding proteins important for cell proliferation [45]. Although global protein synthesis also appears to be enhanced by eIF3h overexpression, it was believed that the specific up-regulation in synthesis of proteins for proliferation was responsible for malignant transformation.

Similar to eIF3a, in a recent large-scale GWAS (genome-wide association study) aiming to identify colorectal cancer susceptibility genes, a variant of eIF3h (rs16892766) was found to associate with colorectal cancer risk with a possibly stronger link in younger (<60 years of age) populations [46]. This SNP is located in the 5′-UTR of the eIF3h gene. This association was also found in colorectal cancer with Lynch syndrome patients and familial colorectal cancer in Dutch populations [47,48]. These studies suggest that eIF3h is the susceptibility gene of colorectal cancer.

eIF3i

eIF3i is an interesting subunit of the eIF3 complex [49] and is also known as TRIP-1 [TGFβ-R (transforming growth factor β receptor) II interacting protein I] [50,51]. Similar to eIF3a, elevated expression level of eIF3i was also found in human cancers, including hepatocelluar carcinoma as well as head and neck squamous cell carcinomas [52,53]. The expression level of eIF3i also increased in cells with transformation induced by the human carcinogen cadmium [54,55]. Ectopic overexpression of eIF3i in Balb/c-3T3 cells caused malignant transformation, and knocking down its expression reversed cadmium-induced malignant transformation [54,55]. Therefore eIF3i is believed to be a proto-oncogene that causes cellular transformation and may mediate cadmium-induced carcinogenesis. However, no further studies have been conducted ever since to examine the mechanism and regulation of eIF3i action in tumorigenesis. However, because eIF3i appears to interact with TGFβ-R, it is tempting to speculate that TGF signalling may mediate or regulate the tumorigenesis function of eIF3i.

In summary, different eIF3 subunits clearly have different roles in cell proliferation and tumorigenesis. While some may serve as a tumour suppressor gene, the others may promote tumorigenesis as proto-oncogenes. It is also worth noting that overexpression of some eIF3 subunits such as eIF3f inhibits mRNA translation [36], contradicting their known role as initiation factors. Down-regulating the expression of other eIF3 subunits such as eIF3a did not severely suppress global translation and may up-regulate the synthesis of some proteins [20,56]. These observations taken together suggest that the eIF3 subunits may not necessarily serve only as a subunit of eIF3 for global translation initiation. They may have other individual functions, such as eIF3i in TGFβ signalling, which are yet to be identified and investigated.

eIF4F

As discussed above, eIF4F is a complex of three proteins, eIF4A, eIF4E and eIF4G, with their various functions in translational initiation from binding the 5′-cap structure of mRNAs to binding eIF3 and PABP. The expression of these proteins has also been found to be associated with human cancers.

eIF4A

There are two eIF4As, eIF4A-1 and eIF4A-2, which share 91% homology [57]. It has been shown that either eIF4A-1 or eIF4A-2 is needed for the formation of the eIF4F complex and that they are interchangeable [58]. The expression of eIF4A-1 has been found to be up-regulated in hepatocellular carcinoma tissues and melanoma cells [59,60]. In melanoma cell lines, whereas eIF4A-1 expression was increased, the expression of eIF4A-2 was not increased as determined using Northern blotting [59]. Although it is not known why only eIF4A1 was up-regulated in melanoma cell lines, it was believed that eIF4A-1 may play a more important role than eIF4A-2 in translational regulation in melanoma. No further studies on whether overexpression of eIF4A-1 or eIF4A-2 is tumorigenic have been reported so far.

eIF4E

eIF4E has been identified as a proto-oncogene and is one of the most well-studied eIFs in cancer cell proliferation. Its elevated expression level had been observed in various human cancers, including cancers of larynx [61,62], breast [6365], cervix [66,67], colon [68,69], oesophagus [70], stomach [71], prostate [72], skin [73], lung [74,75], head and neck [12,76,77], as well as in lymphoma [7] and leukaemia [78]. Ectopic overexpression of eIF4E induced malignant transformation of NIH 3T3 cells as determined by formation of transformed foci on a monolayer of cells and anchorage-independent growth in soft agar [79]. NIH 3T3 cells with eIF4E overexpression could also develop tumours in nude mice. Subsequently, eIF4E expression was shown to relate to tumorigenesis in the immortalized CHO (Chinese-hamster ovary), CREF, HeLa, LS-174T and Th lymphocyte cell lines [69,8084]. Thus eIF4E is likely to be an oncoprotein.

eIF4E may also play a role in tumour invasion and metastasis [3]. Graff et al. [85] showed that the ability of pulmonary metastases was reduced in mice by reducing eIF4E expression. It was also found that reducing eIF4E expression correlated with decreased expression of the metastasis-associated 92 kDa collagenase type-IV and CD44(6v) (exon-6 variants of the CD44 adhesion molecule) but inversely correlated with the increased levels of the putative metastasis-suppressor protein nm23 [85]. Although remaining to be determined, it is possible that eIF4E regulates the expression of these genes by affecting the translation of their mRNAs, which, in turn, regulate metastasis.

eIF4G

As discussed above, eIF4G is a scaffolding protein that is responsible for the assembly of the eIF4F complex. There are two eIF4G isoforms, eIF4G-1 and eIF4G-2, in mammals with 50% identity and their genes have been mapped to 3q27.1 and 11p15 respectively [86]. The expression of both eIF4G-1 and eIF4G-2 has been found to correlate with cancers. However, unlike eIF4G-1, eIF4G-2 does not bind to eIF4E and PABP and likely does not play a role in initiation of cap-dependent translation as a scaffold protein [87,88]. However, eIF4G-2 has been believed to play a role in stimulating protein synthesis initiated from IRESs (internal ribosome entry sites) for death-related genes, including those for c-Myc, Apaf-1 (apoptotic protease-activating factor 1), DAP5 (death-associated protein 5) and XIAP (X-linked inhibitor of apoptosis) [89], although IRES-mediated translation initiation of cellular mRNAs has been in dispute and is arguable [9093].

The 3q27.1 region where the eIF4G-1 gene is located was found to be amplified in human cancers of lung [94], prostate [95], cervical [96], as well as head and neck [97]. The elevated expression of the eIF4G-1 gene has also been found in squamous cell lung cancer and inflammatory breast cancers [98,99], possibly due to gene amplification. Ectopic overexpression of eIF4G-1 caused malignant transformation of NIH 3T3 cells as determined by analysis of foci formation, anchorage-independent growth, and tumour formation in nude mice [100]. Based on these observations, it was believed that eIF4G-1 is also an oncogenic protein and its overexpression may contribute to tumorigenesis.

eIF4G-2 was also known as NAT1 [novel APOBEC-1 (apolipoprotein B mRNA-editing enzyme catalytic polypeptide-1) target 1], p97 and DAP5 [87,101]. Unlike eIF4G-1, the expression of eIF4G-2 is frequently lost in human cancers. The chromosome 11p15 region where the eIF4G-2 gene is located is frequently deleted in invasive bladder cancers [102,103], indicating that this region may harbour important tumour suppressor genes and that eIF4G-2 may be one of these genes. Indeed, eIF4G-2 expression in transitional cell carcinoma of bladder was decreased as determined using DDRT–PCR (differential display reverse transcription–PCR) and real-time PCR [104]. It is thus possible that eIF4G-2 functions as a tumour suppressor. It is currently unknown how the two homologous proteins, eIF4G-1 and eIF4G-2, can have such a different role in cell biology.

Taken together, eIF4A-1, eIF4E and eIF4G-1 are important for initiation of cap-dependent translations and they may also function as proto-oncogenes. However, only the overexpressions of eIF4E and eIF4G-1 are known to promote tumorigenesis. On the other hand, eIF4G-2 does not appear to play a role in cap-dependent translation initiation and it may be a candidate tumour suppressor gene, whereas eIF4A-2 has not been found to associate with cancers.

eIFs AND CANCER PROGNOSIS

In addition to their potential role in tumorigenesis, some eIFs have been shown to associate with cancer prognosis (Table 2). In a study of invasive cervical tumours using immunohistochemistry, patients with high eIF3a level had longer relapse-free survival than those with low eIF3a expression [16]. eIF3a expression appeared to be highest in low-grade cervical intraepithelial neoplasms but low in high-grade tumours, suggesting that eIF3a expression may decrease as tumour progresses. In another study of oesophageal squamous-cell carcinoma using immunohistochemistry and Western-blot analyses, it was found that well-differentiated tumours had high eIF3a expression level and patients with high eIF3a level had fewer tumour metastases and better overall survival [17]. These findings together show that eIF3a may be a factor of good prognosis of cervical and oesophageal cancers although its elevated expression may promote tumorigenesis.

Table 2
eIFs and cancer prognosis
eIFCancerPrognosisReference(s)
eIF3a Cervical cancer Good [16
 Oesophageal squamous-cell carcinoma Good [17
eIF3e Non-small cell lung cancer Poor [34
eIF3h Non-small cell lung cancer Good [44
 Prostate cancer Poor [41
eIF4E Breast cancer Poor [63,65,105107
 Prostate cancer Poor [72
 Colorectal cancer Poor [71
 Lung cancer Poor [74,108
 Neck and brain cancer Poor [61,62,76,109,110
eIF6 Ovarian serous carcinomas Good [112
eIFCancerPrognosisReference(s)
eIF3a Cervical cancer Good [16
 Oesophageal squamous-cell carcinoma Good [17
eIF3e Non-small cell lung cancer Poor [34
eIF3h Non-small cell lung cancer Good [44
 Prostate cancer Poor [41
eIF4E Breast cancer Poor [63,65,105107
 Prostate cancer Poor [72
 Colorectal cancer Poor [71
 Lung cancer Poor [74,108
 Neck and brain cancer Poor [61,62,76,109,110
eIF6 Ovarian serous carcinomas Good [112

As discussed above, the truncated eIF3e may be a proto-oncogene. However, the truncated eIF3e may also be a marker predicting poor prognosis. In a study of the expression of the truncated eIF3e in 101 non-small cell lung cancer patients using real-time PCR, it was found that the truncated eIF3e expression was the independent factor to predict poor prognosis as well as overall and disease-free survival [34]. eIF3h is another eIF3 subunit that has been associated with cancer prognosis response [44]. In this study of 54 non-small cell lung cancer patients, individuals with increased copy number of eIF3h gene in theirs tumours appeared to be more sensitive to gefitimib and had a longer time to progression, as well as longer survival time. However, in another study of 461 prostate cancer patients, eIF3h expression was found to correlate with poor prognosis as determined using fluorescence in situ hybridization and tissue microarray [41]. Thus to find out whether the correlation of eIF3h with good and poor prognosis is tumour-specific clearly needs more studies.

Like its role as a proto-oncogene, the role of eIF4E as a poor prognosis marker of cancers has also been well established. Patients with high eIF4E expression usually have greater risk of recurrence and metastasis of cancers of breast [63,65,105107], prostate [72], colon [71], lung [74, 108], neck and brain [61,62,76,109,110]. One of these studies is a prospective analysis of eIF4E expression and outcome where specimens of 191 stages 1–3 breast cancer patients were accrued and eIF4E was quantified by Western blotting. It was found that patients with high eIF4E expression had a 7.2-fold higher risk of recurrence and 7.3-fold higher risk of cancer-related death than subjects with low eIF4E expression [106]. Together, all these studies clearly showed that eIF4E overexpression is a marker of poor tumour prognosis.

Another interesting factor associated with prognosis is eIF6, an anti-association factor that binds to the 60S ribosome subunit and prevents the re-association of the 40S and 60S ribosome subunits [111]. In a study of 66 ovarian serous carcinomas using microarray and real-time PCR to detect eIF6, it was found that low eIF6 expression correlates with reduced disease-free survival. However, the eIF6 status did not correlate with overall patient survival [112]. Thus eIF6 may relate to only short-term survival of ovarian cancers.

MECHANISMS OF eIF ACTION IN TUMORIGENESIS

Although eIFs may be involved in malignant transformation and prognosis, the molecular mechanisms for these processes still remain largely unknown. Currently, there are two hypotheses regarding the mechanism of eIFs in translational regulation that in turn controls cell growth. One hypothesis is that many mRNAs encoding proteins in the growth-promoting pathway are inefficiently translated and that global enhancement of the translation of these mRNAs results in an imbalance in the levels of their proteins compared with growth-retarding proteins [113]. The other hypothesis is that eIFs regulate translation of a subset of specific mRNAs that play important roles in many essential cellular processes, including proliferation, apoptosis, angiogenesis and DNA repair, and altered eIF expression will up- or down-regulate the expression level of these proteins, which ultimately result in the change of cellular phenotype including cancer [2] (see also Figure 2 and Table 3).

Mechanisms of eIF action in tumorigenesis

Figure 2
Mechanisms of eIF action in tumorigenesis

(A) Enhanced translation of weak mRNAs by increased expression of eIFs. Many mRNAs encoding proteins in the growth-promoting pathway are inefficiently translated, and global enhancement of the translation of these mRNAs by increased expression of eIFs such as eIF4E results in an imbalance in the levels of their proteins compared with growth-retarding proteins. (B) Differential effect of eIFs on different subpopulations of mRNAs. Different subsets of mRNAs are regulated differently by eIFs. Increased expression of eIFs such as eIF3a increases the translation of some mRNAs such as RRM2 but decreases the translation of p27. Many of these mRNAs are yet to be identified.

Figure 2
Mechanisms of eIF action in tumorigenesis

(A) Enhanced translation of weak mRNAs by increased expression of eIFs. Many mRNAs encoding proteins in the growth-promoting pathway are inefficiently translated, and global enhancement of the translation of these mRNAs by increased expression of eIFs such as eIF4E results in an imbalance in the levels of their proteins compared with growth-retarding proteins. (B) Differential effect of eIFs on different subpopulations of mRNAs. Different subsets of mRNAs are regulated differently by eIFs. Increased expression of eIFs such as eIF3a increases the translation of some mRNAs such as RRM2 but decreases the translation of p27. Many of these mRNAs are yet to be identified.

Table 3
Representative mRNAs under translational control by eIFs
mRNARegulatorReference(s)
GCN4 (general control non-derepressible 4) eIF2 [150
ATF4 (activating transcription factor 4) eIF2 [151
α-Tubulin eIF3a [56
p27kip1 eIF3a [56
RRM2 eIF3a [20
Cyclin D1 eIF4E [152,153
VEGF (vascular endothelial growth factor) eIF4E [80,124
FGF-2 eIF4E [80,124,154
c-myc eIF4E [81
ODC eIF4E [82,115
TLK1B (Tousled-like kinase 1B) eIF4E [155,156
MMP-9 (matrix metalloproteinase-9) eIF4E [157
Ribonucleotide reductase eIF4E [158
p120 catenin eIF4G-1 [99
mRNARegulatorReference(s)
GCN4 (general control non-derepressible 4) eIF2 [150
ATF4 (activating transcription factor 4) eIF2 [151
α-Tubulin eIF3a [56
p27kip1 eIF3a [56
RRM2 eIF3a [20
Cyclin D1 eIF4E [152,153
VEGF (vascular endothelial growth factor) eIF4E [80,124
FGF-2 eIF4E [80,124,154
c-myc eIF4E [81
ODC eIF4E [82,115
TLK1B (Tousled-like kinase 1B) eIF4E [155,156
MMP-9 (matrix metalloproteinase-9) eIF4E [157
Ribonucleotide reductase eIF4E [158
p120 catenin eIF4G-1 [99

The most supporting evidence for the first hypothesis came from studies of eIF4E. Because eIF4E is the least abundant initiation factor, cellular mRNAs must compete with each other to bind with eIF4E for translation initiation. Thus the mRNAs with a short and unstructured 5′-UTR (strong mRNA) are able to bind eIF4E more competitively and are consequently translated more efficiently. On the other hand, mRNAs with a long, GC-rich and structured 5′-UTR (weak mRNA) are inefficiently translated. Some proteins involved in growth, survival and angiogenesis are generally encoded by less competitive or weak mRNAs [3]. Therefore the translation of these mRNAs is normally repressed. However, abnormally overexpressing eIF4E would enhance the translation of these weak mRNAs and consequently lead to abnormal cell proliferation and malignant transformation. The following paragraphs highlight examples of these weak mRNAs that have been well studied and demonstrated to be under eIF4E control.

ODC (ornithine decarboxylase) is the first and key regulatory enzyme in polyamine biosynthesis and plays an important role in regulating cell proliferation and oncogenesis [114]. Overexpression of ODC in NIH 3T3 cells resulted in malignant transformation and the transformed cells could form tumours in mouse rapidly [114]. The mRNA of ODC has a long 5′-UTR with complex secondary structures, which largely inhibit its translation [115]. Overexpression of eIF4E could rescue this inhibition and yield a high expression level of ODC [116]. In addition, depleting eIF4E resulted in suppression of ODC expression in the transformed CREF cells induced by Ras [82]. Furthermore, microarray analysis of human breast cancer tissues revealed that eIF4E expression correlated strongly with ODC expression [117], suggesting that the regulation of ODC by eIF4E may occur in human tumours too.

c-myc is a well-known oncogene that is involved in cell growth, proliferation and apoptosis [118]. Its mRNA also possesses a long and structured 5′-UTR, a potential target of eIF4E regulation. It had been reported that overexpression of eIF4E in CHO and Fischer rat embryo CREF cells caused increased expression of c-myc [81]. Interestingly, the promoter region of the eIF4E gene contains a CACGTG box repeats which is a binding site of c-myc and respond to c-myc. EMSA (electrophoretic mobility-shift assay) also showed quantitative binding to this motif that correlated with c-myc levels. Furthermore, mutating this box of eIF4E altered c-myc binding ability, indicating that the transcription of eIF4E gene is under the regulation of c-myc [114]. Therefore eIF4E and c-myc may have a feed-forward loop that co-ordinately contributes to malignant transformation and tumorigenesis [118,119]. This feed-forward loop between eIF4E and c-myc links together transcription and translation, and molecules that affect c-myc or eIF4E function may serve as rheostats of this loop. They may be able to properly tune the outcome of this loop in tumorigenesis.

Supporting evidence for the second hypothesis was mostly from studies on eIF3a, which was shown to regulate the translation of mRNAs of α-tubulin, p27kip1 and RRM2 (ribonucleotide reductase M2) in opposite directions [20,56]. Increasing eIF3a expression increased the synthesis of RRM2 but decreased that of p27kip1 and vice versa. This regulation by eIF3a was believed to depend on the 5′- and 3′-UTR of RRM2 and p27kip1. p27kip1, a CDK (cyclin-dependent kinase) inhibitor and key determinant for the G1 phase cells entering S-phase, is a known tumour suppressor. The negative regulation of p27kip1 by eIF3a is consistent with a possible role for eIF3a in tumorigenesis. RRM2 is another potential downstream mediator of eIF3a function in tumorigenesis. RRM2 plays a crucial role in converting ribonucleotides into their corresponding deoxyribonucleotides, which is a rate-limiting step of DNA synthesis. Overexpression of RRM2 in H-Ras-transformed fibroblasts increased their growth efficiency in soft agar, tumour growth rates in syngeneic mice and elevated metastatic potential [120]. Down-regulating RRM2 expression by antisense cDNA reduced the malignant level of cancer cells [121]. These findings taken together demonstrate that eIF3a regulates the translation of different subpopulations of mRNAs in different directions in favour of cell proliferation and possibly tumorigenesis.

In addition to the above two main mechanisms of eIF involvement in tumorigenesis by regulating translation of specific or global weak mRNAs, other mechanisms of eIF involvement in tumorigenesis without translational control have also been proposed. For example, eIF3i not only can associate with TGFβ-R II, but is also phosphorylated by TGFβ-R II [50]. It appears that eIF3i expression could modulate TGFβ signalling in both receptor-dependent and -independent pathways [51]. In addition, it has also been found that inhibition of mTOR (mammalian target of rapamycin) kinase reduced the serine phosphorylation of eIF3i, resulting in reversion of the malignant transformation induced by eIF3i overexpression [122]. These findings suggest that eIF3i may be involved in carcinogenesis through multiple pathways. However, to find out whether these pathways involve translational regulation by eIF3i requires further investigation.

eIFs AS NEW CANCER THERAPEUTIC TARGETS

As the detailed mechanisms of eIF action in regulating gene expression is slowly being revealed, the involvement of deregulated eIF expression in cell proliferation and malignant transformation had made them a group of interesting and attractive targets for cancer therapeutic interventions (Table 4).

Table 4
Pharmacological agents targeting eIFs
Compound or strategyTargetReference(s)
Antisense RNA eIF4E [123125
Suicide gene eIF4E [127129
eIF4E antisense oligonucleotides eIF4E [126
4EGI-1 eIF4E [132
Ribavirin eIF4E [78
5′-H-Phosphonate derivatives eIF4E [131
Pateanmine eIF4A [138,139
Salubrinal eIF2α [146
Compound or strategyTargetReference(s)
Antisense RNA eIF4E [123125
Suicide gene eIF4E [127129
eIF4E antisense oligonucleotides eIF4E [126
4EGI-1 eIF4E [132
Ribavirin eIF4E [78
5′-H-Phosphonate derivatives eIF4E [131
Pateanmine eIF4A [138,139
Salubrinal eIF2α [146

For therapeutic interventions, eIF4E has been occupying centre stage. Antisense DNAs or siRNAs (small interfering RNAs) have been tested in proof-of-principle studies and are currently in clinical trials [85,123126]. Inhibiting eIF4E expression with these approaches clearly reversed the malignant phenotype of the tumour cells both in vitro and in vivo. However, their use has several major drawbacks for clinical development including toxicity, efficacy and stability, and difficulty in delivery. Nevertheless, Eli Lilly and Company developed a second-generation antisense oligonucleotide targeting eIF4E that appears to be able to reduce tumour growth in mice without toxicity [126]. This second-generation antisense oligonucleotide may have the potential to be developed for clinical use.

Because eIF4E may be responsible for up-regulating the translation of weak mRNAs in cancer cells, resulting in imbalance in expression of growth-promoting and -inhibiting genes, gene therapy based on this concept has been tested. DeFatta et al. [127] inserted the 5′-UTR of FGF-2 (fibroblast growth factor 2), a gene with weak mRNA, upstream of the HSV-TK (herpes simplex virus type-1 thymidine kinase gene), and they found that cancer cells expressing the chimaeric RNA were more sensitive to gancyclovir than control cells. Two other groups also did similar investigations using lentivirus and adenovirus delivery systems. In the study by Yu et al. [128], a lentiviral vector containing HSV-TK with a DNA sequence encoding a short 5′-UTR was engineered. Normal cells harbouring this plasmid need >100-fold more gancyclovir to be killed than cancer cells harbouring this gene [128], suggesting that the suicide gene is more easily translated in cancer cells. In the second study, Mathis et al. [129] engineered the same suicide gene and 5′-UTR into an adenovirus vector and showed the increased gancyclovir cytotoxicity to cancer cells compared with normal cells. Thus this strategy of gene therapy by taking advantage of eIF4E up-regulation in cancer cells may provide a new way of treating human cancers.

Targeting the binding of eIF4E to the 5′-cap structure of mRNAs or eIF4G has also been considered. Based on the co-crystal structure of eIF4E bound with 7-methyl-GDP [130], it was thought that compounds of 5′-cap analogues might have the potential of inhibiting eIF4E function and cap-dependent translation initiation. Indeed, Ghosh et al. [131] screened a small library of 7-methylguanosine nucleoside and nucleotide analogues to determine their ability to inhibit eIF4E in cell-free assays. They found that the constrained 5′-H-phosphonate derivatives of 7-methylguanosine nucleoside were potentially cell-permeable inhibitors of eIF4E [131]. However, none of these derivatives have been tested as to whether they are active in cells and specific to cancer cells. Clearly, there is a lot of work to be done with this type of inhibitors.

As discussed above, eIF4E binds to eIF4G to form the eIF4F complex and mediates the binding of this complex to the 5′-cap structure of mRNAs. In a recent high-throughput screening for small molecule compounds that inhibit binding of a peptide derived from eIF4G-1 to eIF4E, Moerke et al. [132] identified a compound, 4EGI-1, that binds eIF4E, disrupts eIF4E–eIF4G association, inhibits cap-dependent translation, inhibits cellular expression of oncogenic proteins encoded by weak mRNAs such as c-Myc and Bcl-XL and exhibits activity against multiple cancer cell lines [132]. Interestingly, this compound effectively enhanced 4E-BP1 (eIF4E-binding protein 1) association with eIF4E both in vitro and in cells. However, preclinical studies using animal models will be needed to further test whether this compound has any potential therapeutic values.

Ribavirin is a triazole carboxamide ribonucleoside and was discovered in the 1970s [133]. Only recently was it found that ribavirin could suppress eIF4E activity by physical mimicry of the 5′ m7GpppN cap and suppress eIF4E-mediated oncogenic transformation [134]. This inhibition reduced the expression level of some oncogenes regulated by eIF4E, such as cyclin D1. Subsequently, it was found that ribavirin specifically binds eIF4E as determined using MS and it affects the Akt (also called protein kinase B) survival signalling pathway by the inhibition of eIF4E function [135,136]. Ribavirin has been tested in a clinical trial of 11 acute myeloid leukaemia patients with daily administration for a 28 day cycle and up to six cycles [78]. One of these patients had complete remission, two with partial remissions, and two with blast responses, four with stable diseases, and two with progressive diseases. It also appears that ribavirin-induced relocalization of nuclear eIF4E to the cytoplasm and reduction of eIF4E levels were associated with clinical responses. Although the sample size in this clinical study was small, the outcome indicates that targeting eIF4E may provide an effective way of eliminating human cancers.

Recently, using an in vitro multiplex translation high-throughput assay, Novac et al. [137] screened >90000 compounds and identified a compound (NSC119889) that inhibited translation initiation. NSC119889 inhibited the binding of ribosomes to mRNAs and prevented translation initiation from the 5′-cap of mRNAs as well as internal initiation of EMCV (encephalomyocarditis virus) and poliovirus IRESs, but not that of the HCV (hepatitis C virus) IRES. This finding suggests that NSC119889 may act on a factor that is not required for the HCV IRES. However, the exact target of NSC119889 is currently unknown.

In another high-throughput screening by the same group, a marine natural product, pateanmine, was identified to target and stimulate eIF4A activity, which in turn inhibits translation initiation [138]. However, it is not known why stimulating the eIF4A helicase activity would inhibit translation initiation. In another study, it was also found that pateanmine stimulated eIF4A activity and inhibited translations [139]. However, the later study also showed that pateanmine could also weaken the interactions between eIF4A and eIF4G and increase the formation of a stable ternary complex between eIF4A and eIF4B. As a result, pateanmine causes the stalling of initiation complexes on mRNA and inhibits translation initiation.

Many eIFs are under regulation by post-translational modifications such as phophorylation. Targeting their upstream kinases or phosphatases is another approach of inhibiting eIFs and mRNA translations for cancer treatment. eIF4E and its regulatory protein 4E-BP are both known downstream targets of mTOR in the PI3K (phosphoinositide 3-kinase)/Akt pathway and targeting the upstream kinases in this pathway will affect the regulation of gene expression with some mTOR inhibitors already tested in clinical trials [140142]. Rapamycin has been shown to cause significant reduction in protein synthesis [143] and suppress the translation of mRNAs that contain a 5′-oligopyrimidine tract [144,145],

Recently, in a study screening for compounds that protect cells from ER (endoplasmic reticulum)-stress-induced apoptosis, salubrinal was identified out of ~19000 compounds as an inhibitor of cellular complexes GADD34 (growth-arrest and DNA-damage-inducible protein 34)–PP1 (protein phosphatase 1) and/or CReP (constitutive repressor of eIF2α phosphorylation)–PP1 that dephosphorylate eIF2α [146]. However, it is currently unknown whether salubrinal inhibits the GADD34–PP1 and CReP–PP1 complexes via direct binding or an indirect signalling event. Furthermore, it remains to be tested whether the inhibition of eIF2α dephosphorylation by salubrinal affects cellular translation initiation of mRNAs. Nevertheless, because the unphosphorylated eIF2α is oncogenic [5], this inhibitor of eIF2α dephosphorylation may also have antitumour activity.

CONCLUDING REMARKS AND PERSPECTIVES

Translational control and eIFs have been shown to play crucial roles in cell cycle, growth, differentiation and tumorigenesis. Some eIFs may also be related to cancer prognosis. Although the exact mechanism of eIF involvement in tumorigenesis and prognosis is not yet clear, it is believed that the altered expression levels of eIFs up- or down-regulate the translation of various mRNAs encoding proteins important for different cellular processes such as cell cycle, proliferation, survival and apoptosis. eIFs have also been slowly recognized as targets for therapeutic discovery and various agents have been identified that inhibit eIFs for development of potential therapeutics.

While many previous studies had a focus on whether and how eIFs contribute to tumorigenesis, only a limited number of studies have been performed that aimed to understand the mechanism of alteration of eIF expression in cancers. Another area worthy of further investigation is whether the 5′-UTR of mRNAs is really responsible for eIF regulation of mRNA translation. If so, what features of the 5′-UTR make the translation of one mRNA go up while the other goes down with the altered expression of eIF. Most recently, it was found that the expression of PRL-3 (phosphatase of regenerating liver-3), a cancer metastasis-related protein, was regulated by PCBP1 [poly(C)-RNA-binding protein 1] via the 5′-UTR of PRL-3 [159]. A triple GCCCAG motif in the 5′-UTR was identified to mediate this regulatory process by binding of PCBP1. However, whether eIF plays similar roles as PCBP1 is not yet known. It is also worth noting that some eIFs may also have functions in addition to their possible regulatory roles in protein synthesis. These additional functions may be important for a variety of cellular processes.

Abbreviations

     
  • CReP

    constitutive repressor of eIF2α phosphorylation

  •  
  • DAP5

    death-associated protein 5

  •  
  • 4E-BP

    eIF4E-binding protein

  •  
  • eIF

    eukaryotic initiation factor

  •  
  • GADD34

    growth-arrest and DNA-damage-inducible protein 34

  •  
  • HCV

    hepatitis C virus

  •  
  • HSV-TK

    herpes simplex virus type-1 thymidine kinase gene

  •  
  • FGF-2

    fibroblast growth factor 2

  •  
  • IRES

    internal ribosome entry site

  •  
  • Met-tRNAi

    initiator methionyl-tRNA

  •  
  • MMTV

    murine-mammary-tumour virus

  •  
  • mTOR

    mammalian target of rapamycin

  •  
  • ODC

    ornithine decarboxylase

  •  
  • PABP

    poly(A)-binding protein

  •  
  • PCBP1

    poly(C)-RNA-binding protein 1

  •  
  • PP1

    protein phosphatase 1

  •  
  • PRL-3

    phosphatase of regenerating liver-3

  •  
  • RRM2

    ribonucleotide reductase M2

  •  
  • SNP

    single nucleotide polymorphism

  •  
  • TGFβ-R

    transforming growth factor β receptor

  •  
  • tRNAMet

    methionine tRNA

  •  
  • UTR

    untranslated region

FUNDING

Our work was supported in part by the National Institutes of Health [grant number R01 CA94961 (to J.-T.Z.)]; the Showalter Research Trust Fund (to Z.D.); the National High-Tech R&D Program of China [grant number 2009AA022704 (to Z.-Q.L.)]; and the National Natural Science Foundation of China [grant number 30873089 (to Z.Q.L.)]. J.Y.Y. was supported in part by the China Scholarship Council, the Graduate Degree Thesis Innovation Foundation of Central South University [grant number 2009ybfz09]; and the Hunan Province Innovation Foundation for Postgraduates [grant number CX2009B060].

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