S100P promotes prostate cancer growth and survival Free

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S100P is a member of the S100 family of proteins and is known to be over-expressed in prostate cancer. Our lab has previously shown that there is a strong correlation between S100P expression and clinical stage of prostate cancer. Our data suggested that S100P might serve as a biomarker and warranted further investigation to determine if S100P would serve as a good drug target. Hence, in the present study, we evaluated the mechanisms by which S100P affects prostate tumor growth in vitro and in vivo. Modulation of S100P levels in prostate cancer cells was done using expression constructs and RNA interference. S100P was over-expressed in PC3 prostate cancer cells, which express low amounts of S100P, by transfection with an S100P expression construct. Stable S100P over-expressing PC3 cells were established. The effects of S100P expression on cell growth were monitored by evaluating proliferation, apoptosis, cell cycle arrest, cell migration and growth on soft agar. Our results indicate that increased S100P levels correlate with the increased rates of prostate cancer cell growth, migration and colony formation on soft agar. Furthermore, S100P overexpressing cells were found to have increased levels of NF-kB translocation when treated with TGF-beta. Moreover, increased S100P levels was also found to confer resistance to chemotherapy. Decreased induction of apoptosis was observed in PC3 cells over-expressing S100P when compared to control PC3 cells treated with 5-fluorouracil and camptothecin. Side by side, S100P levels were reduced in 22Rv1 prostate cancer cells, which express higher levels of S100P, by small interfering RNA gene silencing. Decreasing S100P levels led to reduced cell growth. Gene expression profile was done to investigate the mechanism by which S100P promotes growth and survival. In vivo studies showed that increased S100P levels led to significantly increased growth of tumors in xenografts in nude mice with subcutaneously implanted S100P over-expressing PC3 cells. Our data supports the growing evidence that S100P is involved in transcriptional regulation and links S100P for the first time to the NF-kB pathway. S100P is now being considered as a putative drug target that will serve as a starting point for the development of new targeted therapies for treatment of prostate cancer.