Importance of PI3K Signalling in Prostate Cancer

Inhibition of the PI3K pathway is an important therapeutic approach for the treatment of prostate cancer. Signalling by the PI3K/Akt/mTOR pathway plays an important role in the survival mechanism of prostate tumours and it is this signalling that is keeping the prostate cancer cells alive. Inhibit this pathway and the cancer cells automatically undergo apoptosis which is programmed cell death. It has been shown that the natural PI3K inhibitor salvestrol Q40 results in reduced downstream phosphorylation of Bcl-2 causing elevated Bax to Bcl-2 ratios that result in apoptosis. Furthermore Zytiga drug resistance pathways are mediated by the PI3K pathway and so inhibitors of PI3K such as salvestrols can be used to overcome Zytiga resistance. A number of different PI3K inhibitors are under clinical investigation in combination with Zytiga.

PI3K Signalling Pathway in Prostate Cancer

Prostate cancer is the second highest cause of male cancer related mortality. Currently the main aim of   therapy for localised and metastatic disease is total androgen blockade. This aim has been achieved with Zytiga which inhibits all androgen production, thereby reducing stimulation of the androgen receptor (AR). This in turn prevents the activation of androgen-regulated genes, which normally result in on-going growth and survival of particular interest in this survival mechanism is the continued signalling by the PI3K pathway. Inhibition of testicular androgen production may be achieved surgically (bilateral orchidectomy) or chemically, using LHRH agonists. The latter induces castrate levels of testosterone by down-regulating pituitary LHRH receptors (and therefore gonadotropin hormone production) through constant stimulation. The action of androgen may be blocked at a peripheral level using anti androgens such as Casodex and Enzalutamide, which inhibit ligand binding to AR and subsequent activation. Although this approach has initial responses the majority of men relapse with castrate resistant prostate cancer (CRPC) and this is the cause of significant morbidity and mortality. To overcome this and to improve patients treatment options the mechanisms of castrate resistance need to be addressed.

The PI3K/Akt cascade regulates several cellular processes such as proliferation and apoptosis. Akt activation results in phosphorylation of multiple substrates and has been implicated in prostate carcinogenesis and castration resistance. Research has suggested that Akt interacts with signalling cascades implemented in carcinogenesis, in particular the NFkB cascade and AR signalling. The current study investigated the hypothesis that the expression and activation of PI3K/Akt cascade influences the progression to castrate resistant disease using clinical prostate cancer tumours. Fluorescent insitu hybridisation and Immunohistochemistry revealed that PTEN deletion was a common event in castrate resistant prostate cancer and low PTEN protein expression was significantly associated with a poor outcome. PTEN negatively regulates PI3K signalling. Consequently increased levels of PI3K and activated Akt (pAkt ser 308 and pAkt ser 473) were significantly associated with a shorter time to biochemical relapse and shorter disease specific survival. Inhibition of PI3K resulted in a significant reduction in cellular proliferation and Akt phosphorylation. The downstream affects of Akt activation were investigated. Akt has been reported to activate the NFkB signalling cascade both directly and indirectly.

Having shown a significant link between expression and activation of the PI3K cascade and progression to castrate resistant disease, the interaction between Akt and the AR was investigated in both clinical prostate tumours and cell lines. The phosphorylation of AR at the Akt consensus site serine 213 (pARser213) was significantly associated with disease progression. Patients with high expression pARser213 had a significantly shorter time to death from relapse and disease specific survival. Additionally 42% of patients displayed an increase in pARser213 expression, these patients also had a significantly shorter time to death from relapse and disease specific survival. Inhibition of PI3K resulted in a reduction of pARser213 expression in both cell lines. This research highlights the impact of both the PI3K/Akt and NFkB signallingcascades on prostate cancer progression and development of castrate resistant disease. In particular this study highlights the impact of Akt phosphorylation in castrate resistant prostate cancer patients. Therefore phosphorylation of AR at serine 213 may serve as a diagnostic tool to predict patient outcome in response to maximum androgen blockade and inhibition of AR 213 phosphorylation via the Akt cascade may be an effective therapeutic avenue to investigate for treatment of prostate cancer. In conclusion inhibition of the PI3K pathway can lead to cancer cell death and therefore has promising therapeutic potential. Inhibition of the PI3K pathway with natural molecules such as salvestrol Q40 and wortmanin has been demonstrated to lead directly to programmed cell death (i.e. apoptosis) of cancer cells leading to regression of primary tumours and metastases in cancer patients. In some cases complete resolution of bone metastases have been reported with these agents.