Phosphatidylinositol 3-Kinase Class IA p110β is the predominate expressed isoform in prostate cancer cell lines and is the major Class IA PI 3-kinase contributor to prostate cancer cell survival.

B105 Prostate cancer is the second leading form of cancer in men and is disproportionably more prevalent among African-American men. Current prostate cancer drug therapies do not include preventive treatments for those at high risk, promote non-compliance due to side effects, and in many cases are not efficient at totally eradicating the disease. Researchers are currently studying cellular targets for drug therapy. This will allow for development of drugs with fewer or no side effects and prevention of prostate cancer cell growth and proliferation. The Phosphatidylinositol 3-kinase (PI 3-kinase) signal transduction pathway has been shown in several studies to be linked to the development and progression of many cancers including prostate cancer. Among its many other functions, PI 3-kinase influences cell survival by preventing apoptosis via its downstream target AKT. This research project investigates how PI 3-kinase expression and activity is altered in DU145, LNCap, and PC3 prostate cancer cell lines. The Class of PI 3-kinase enzymes, Class IA, shown to be linked to prostate cancer is composed of a regulatory subunit, p85, and a catalytic subunit, p110. The prostate cancer cell lines used in these studies express two Class IA isoforms, p110α and p110β. Studies have shown that these isoforms have specific cellular functions and are not redundant. Therefore, it is possible that one or both isoforms are responsible for the increased PI 3-kinase activity seen in prostate cancer cells that leads to an increase in cell survival. In designing the appropriate drug target, we must understand which PI 3-kinase isoforms are involved in prostate cancer development and progression. The approach taken in this investigation was to determine basal expression of each isoform in these cell lines and then use interference RNAs to specifically reduce each isoform expression. Specific reduction of each isoform expression was achieved. The effect of loss of an isoform expression on AKT signaling and apoptosis was then examined. We found that p110β isoform is predominately expressed in DU145, LNCap, and PC3 cell lines. Loss of p110β expression in all prostate cancer cell lines significantly reduced AKT activity and promoted an increase in apoptosis. The reduction of p110α expression was not as significant as p110β reduction effects. Interestingly, in DU145 cells reduction of p110α promoted a feedback up regulation of p110β expression and a subsequent increase in AKT activation, not a reduction. This implies that p110β and not p110α is closely associated with AKT activation in prostate cancer cells. In conclusion, p110β is the major Class IA contributor to PI 3-kinase linked prostate cancer cell survival activity. These results aid in better understanding how PI 3-kinase signaling is altered in prostate cancer. Future studies that further examine Class IA isoform specific involvement in prostate cancer will advance our knowledge of how to efficiently target detrimental and unregulated PI 3-Kinase activities for prostate cancer drug therapy.