Regulation of telomerase by genistein in human prostate cancer cells
Chau, My N.
Thesis (Ph.D.)--Georgetown University, 2008.; Includes bibliographical references. Genistein, the most abundant isoflavonoid found in soy and other leguminous plants such as lentils, has cancer growth modulating effects that vary based on its concentration. It is unclear which particular concentrations of genistein have a cancer promoting or cancer inhibiting effect. The mechanism for enhanced cancer cell proliferation by genistein is also unknown. One molecular target of genistein is telomerase. Telomerase imparts endless replicative potential to cancer cells by facilitating proliferation and survival through the alteration of growth factors and apoptotic proteins. Having previously determined that pharmacological concentrations of genistein repress telomerase activity and prostate cancer cell growth, we examined the effect of physiologically achievable concentrations of genistein on telomerase activity and cancer cell proliferation. We found that physiologically achievable concentrations of genistein enhance telomerase activity and human prostate cancer cell growth. Signal transducers and activators of transcription 3 (STAT3) activation and increased STAT3 binding to the telomerase reverse transcriptase (TERT) promoter by physiological concentrations of genistein were identified as the mechanism for enhanced telomerase activity in human prostate cancer cells.; The mechanism for genistein-induced activation of STAT3 was then determined. A physiological concentration of genistein activated signaling proteins upstream of STAT3 including JAK2, Akt, Src, and MAPK p44/42 in human prostate cancer cells. Specific shRNA inhibition of these signaling proteins in stable STAT3 reporter prostate cancer cells reduced STAT3 reporter activity and cancer cell proliferation. Genistein treatment of cells with the signaling proteins inhibited did not increase STAT3 reporter activity and cancer cell proliferation to the level observed in genistein treated control cells, indicating that JAK2, Akt, Src, and MAPK p44/42 are necessary for genistein-induced activation of STAT3. The data collectively suggests that physiologically achievable concentrations of genistein enhance cancer cell proliferation by increasing telomerase activity via STAT3 activation mediated by upstream signaling proteins. The result that physiological concentrations of genistein promote prostate cancer cell growth indicates that prudence should be exercised when genistein is considered for chemotherapeutic purposes as unfavorable effects in individuals with prostate cancer is possible.
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