Loss of function of the PTEN tumour suppressor, resulting in dysregulated activation of the phosphoinositide 3-kinase (PI3K) signalling network, is recognized as one of the most common driving events in prostate cancer development. The observed mechanisms of PTEN loss are diverse, but both homozygous and heterozygous genomic deletions including PTEN are frequent, and often accompanied by loss of detectable protein as assessed by immunohistochemistry (IHC). The occurrence of PTEN loss is highest in aggressive metastatic disease and this has driven the development of PTEN as a prognostic biomarker, either alone or in combination with other factors, to distinguish indolent tumours from those likely to progress. Here, we discuss these factors and the consequences of PTEN loss, in the context of its role as a lipid phosphatase, as well as current efforts to use available inhibitors of specific components of the PI3K/PTEN/TOR signalling network in prostate cancer treatment.

Despite the development of a wide range of therapies, heart failure remains a leading cause of death in Western society. New therapies are needed to help combat this debilitating condition. Exercise is becoming an increasingly important feature of rehabilitation programmes for patients with heart failure. Before the 1980s, patients with heart failure were advised not to exercise as it was thought that exercise would increase the risk of a cardiac event (such as myocardial infarction). However, in recent years both aerobic and resistance training have been shown to be safe and beneficial for patients with heart failure, improving exercise tolerance and quality of life, and preventing muscular deconditioning. The molecular mechanisms responsible for exercise-induced cardioprotection are yet to be elucidated, however studies in transgenic mice have identified PI3K(p110α) (phosphoinositide 3-kinase p110α) as a likely mediator. PI3K(p110α) is a lipid kinase which is activated in the heart during chronic exercise training, and is important for maintaining heart structure and function in various pathological settings. In the present review the protective effects of PI3K(p110α) in the failing heart and its potential as a therapeutic strategy for the treatment of heart failure is discussed.

GSEs (grape seed extracts) which contain polyphenolic compounds cause an endothelium-dependent relaxation of blood vessels. The aim of the present study was to examine the mechanisms involved in this response. A well-characterized GSE was applied to rabbit aortic rings suspended in organ baths containing Krebs–Henseleit buffer maintained at 37 °C. In aortic rings pre-contacted with noradrenaline (norepinephrine), the extract produced a dose-dependent relaxation. The maximum relaxations elicited by the extract (71.9±1.0%) were similar to those elicited by acetylcholine (64.2±1.5%) ( n =12 for each). As expected, the relaxations were abolished by removal of the endothelium and by prior incubation with L -NAME ( N G -nitro- L -arginine methyl ester), confirming the essential role of eNOS (endothelial NO synthase) in the response. The responses to the GSE were also abolished by incubation with wortmannin and LY294002, which are inhibitors of PI3K (phosphoinositide 3-kinase). These compounds had no effect on the responses to acetylcholine. Using immunoblotting, we also demonstrated that the GSE induced the phosphorylation of both Akt and eNOS in HUVECs (human umbilical vein endothelial cells). Finally, the extract was modified by methylation of the hydroxy groups in the polyphenolic groups and was applied to the aortic rings. The modified extract failed to cause a relaxation. Taken together, these findings suggest that the endothelium-dependent relaxation induced by the GSE was mediated by activation of the PI3K/Akt signalling pathway through a redox-sensitive mechanism, resulting in phosphorylation of eNOS.

Albumin has complex effects on PTECs (proximal tubular epithelial cells) and is able to stimulate growth or injury depending on its bound moieties. Albumin itself is a mitogen, inducing proliferation through a number of pathways. In PTEC exposed to purified albumin, polyamines are required for entry into the cell cycle and are critical for proliferation. Polyamines are synthesized from L -ornithine (itself derived by the action of arginase on L -arginine), and the transport and availability of L -arginine may thus be important for subsequent polyamine-dependent proliferation. In the present study we investigated radiolabelled cationic amino-acid transport in cultured PTEC exposed to 20 mg/ml ultrapure recombinant human albumin, describing the specific kinetic characteristics of transport and the expression of transporters. L -[ 3 H]Arginine transport capacity in human PTEC is increased after exposure for 24 h to human albumin, mediated by the broad-scope high-affinity system b 0,+ and, to a lesser extent, system y + L (but not system y + ) transport. Increased transport is associated with increased b 0,+ -associated transporter expression. Inhibition of phosphoinositide 3-kinase, a key regulator of albumin endocytosis and signalling, inhibited proliferation, but had no effect on the observed increase in transport. PTEC proliferated in response to albumin. L -Lysine, a competitive inhibitor of L -arginine transport, had no effect on albumin-induced proliferation; however, arginine deprivation effectively reversed the albumin-induced proliferation observed. In conclusion, in PTEC exposed to albumin, increased L -arginine transport is mediated by increased transcription and activity of the apical b 0,+ transport system. This may make L -arginine available as a substrate for the downstream synthesis of polyamines, but is not critical for cell proliferation.