The role of PI3K isoforms

The catalytic isoform p110ß and its regulatory complex p85a have been shown to mediate AR transactivation in the presence of androgens [137]. Overexpression of wild type p110ß led to androgen-independent AR transactivation while the overexpression of p110a gene showed no effects. Interestingly, short interference RNA (siRNA) disruption of p110ß gene in prostate cancer cells abrogated tumor progression in vivo. Moreover, clinical analysis of tumor samples linked high p110ß and p85a expression at the mRNA and protein level to malignant prostate tumors, metastasis and poor differentiation.

Conditional knockout mouse models of p110ß have further provided insight into the onco-genic potential of the catalytic subunit. Prostate epithelium remained normal in the absence p110ß alone while PTEN loss alone resulted in tumor growth in the anterior lobe by 12 weeks; subsequent ablation of the p110ß gene rescued PTEN null anterior prostate from tumorigenesis [138]. Increased phosphorylation of Akt on Ser473 was achieved through PTEN loss while additional ablation of p110ß attenuated Akt activation. These results are not attributable to changes in the p110a subunit as minimal changes in tumor growth and Akt phosphorylation were observed upon p110a ablation. One study ascribed the differential functions of the p110a and p110ß catalytic subunits to the distinct pools of PIP3 they generate [139]. The p110a, in response to growth factor stimuli, will cause an immediate flux of PIP3 coupled with efficient Akt phosphorylation, whereas p110ß will maintain a basal level of PIP3 with minimal effects on Akt phosphorylation. Together with the observation that p110ß-specific inhibitors effectively reduce Akt phosphorylation in the absence of PTEN in vitro [139], oncogenic transformation of prostate cancer cells upon PTEN loss is likely derived from the p110ß-catalyzed pool of PIP3 [138]. These data collectively support distinct functionalities of the p110a and p110ß catalytic subunits in PI3K/AKT signaling.

Recent studies have also shed light onto the third isoform of PI3K catalytic subunit, p1105. Tzenaki et al., (2012) reported CaP cells that contain high levels of p1105 activity have dampened PTEN functionality. Treatment with p1105 -specific inhibitor in DU145 cells promoted PTEN activation, reduced Akt phosphorylation and inhibited cell proliferation. In another cell line (22Rv1) with wild-type PTEN and low p1105 expression, measured basal PTEN activity was comparatively higher than that in DU145 cells. Inhibition of p1105 in 22Rv1 likewise did not affect Akt phosphorylation status or cell proliferative abilities. Hence, the development of p1105 -selective inhibitors may hold promise since blocking p1105 activity will also indirectly inhibit other catalytic isoforms through PTEN activation.

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