Epinephrine-Induced and Antiapoptotic Signaling in Prostate Cancer
Annual rept. 1 May 2008-30 Apr 2009
WAKE FOREST UNIV WINSTON-SALEM NC SCHOOL OF HEALTH SCIENCES
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We hypothesize that epinephrine released after emotional stress activates anti-apoptotic signaling pathways in prostate tumors, and contributes to the resistance of advanced prostate cancer to therapies. To test this hypothesis, we propose to examine if stressepinephrine induces the activation of PKA and BAD phosphorylation in prostate tumors and determine if stressepinephrine reduces therapeutic efficacy of anti-cancer treatments. We have developed methodologies to test the role of beta2-AR in stress-induced activation of PKA. PKA activity could be judged by phosphorylation of CREB and BAD. Although BAD phosphorylation is more relevant to antiapoptotic effect of epinephrine, CREB could be used as biomarker of PKA activation. Still, additional experiments are needed to reliably monitor activation of PKA and BAD phosphorylation in xenograft tumors in vivo. Since C42 cells are PTEN deficient, PI3KAkt pathway is constitutively active and BAD is constitutively phosphorylated in these cells. Thus, to determine whether BAD could be phosphorylated by stressepinephrine in vivo we need to inhibit PI3K in C42 xenografts. To accomplish this two approaches are under way first, to use new PI3K inhibitor ZSTK474, second to generate cells that inducibly express PTEN phosphatase.
- Medicine and Medical Research
- Organic Chemistry