XIAP & Phactr 4: NOVEL AMPK DOWNSTREAM TARGETS IN PROSTATE CANCER

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2019-05

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Prostate cancer is the second leading cause of cancer related death in American men. The androgen receptor (AR), a nuclear receptor, is the central driver of prostate cancer. AR interacts with specific androgen response elements that control the expression of androgen target genes. Our lab identified the AR-CaMKK2-AMPK pathway as a promoter of prostate cancer progression. 5' AMP activated protein kinase (AMPK) plays a key role in cellular energy homeostasis. Recent studies have revealed that AMPK is involved in the progression of prostate cancer. Using a bioinformatics approach that combined clinical phospho-proteomics data with a new AMPK phosphorylation motif, we identified potential new targets that we hypothesize may be functional drivers of the disease. XIAP and Phactr4 were two putative AMPK downstream targets that were studied to be involved in prostate cancer progression. AMPK-mediated phosphorylation of XIAP and Phactr4 were investigated using immunoprecipitation. RNA interference through small interfering RNA (siRNA) targeted on AMPK and prostate cancer cells engineered to inducibly knockdown CaMKK2 (enzyme involved in phosphorylation of AMPK) by shRNA were used to determine the CaMKK2-AMPK action on XIAP and Phact4. The experiments suggested that XIAP could be phosphorylated by CaMKK2 in an AMPK-independent fashion and was demonstrated in the PTEN wild type 22RV1 cell line. Also, it was suggested that the phosphorylation of Phactr4 could be affected by knock down of CaMKK2. Proliferation assays suggested a significant role for Phactr4 in advanced prostate cancer cell survival as a knock down of Phactr4 through RNA interference significantly decreased proliferation.

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