Functional evidence implicating S100P in prostate cancer progression

Abstract

S100P protein regulates calcium signal transduction and mediates cytoskeletal interaction, protein phosphorylation and transcriptional control. We have previously shown how elevated S100P levels in prostate cancer strongly correlate with progression to metastatic disease. In our study, we evaluated the functional significance of S100P expression on prostate tumor growth in vitro and in vivo. S100P levels were modulated by overexpressing S100P in PC3 prostate cancer cells and by silencing S100P levels in 22Rv1 prostate cancer cells. Overexpression of S100P in PC3 cells promoted cell growth, increased the percentage of S-phase cells, decreased basal apoptosis rate and promoted anchorage independent growth in soft agar. Furthermore, prostate cancer cells overexpressing S100P were protected against camptothecin-induced apoptosis. Conversely, silencing of S100P in 22Rv1 cells using siRNA resulted in a prominent cytostatic effect. The influence of S100P on tumor growth and metastases were assessed in vivo. S100P-overexpressing PC3 cells had a dramatically increased tumor formation compared to controls. Microarray analysis showed the involvement of growth pathways including increased androgen receptor expression in S100P-overexpressing cells. These results provide the first functional proof that S100P overexpression can upregulate androgen receptor expression and thereby promote prostate cancer progression by increasing cell growth. Moreover, the results confirm the oncogenic nature of S100P in prostate cancer and suggest that the protein may directly confer resistance to chemotherapy. Hence, S100P could be considered a potential drug target or a chemosensitization target, and could also serve as a biomarker for aggressive, hormone-refractory and metastatic prostate cancer. ' 2008 Wiley-Liss, Inc.Key words: prostate cancer; S100P; xenograft Cancer of the prostate is the second leading cause of cancer deaths amongst men in the United States. 1 Initially, the disease responds to androgen blockade therapy, however, resistance to this hormone therapy often develops during tumor progression. Hormone-refractory tumors are also often metastatic and resistant to chemotherapy and thus present a significant clinical problem. Predictive biomarkers of prostate tumor progression, as well as new therapeutic interventions for advanced stages of prostate cancer are urgently needed. The application of microarray technologies by our group, as well as others, to interrogate the prostate cancer genome has proven to be a powerful approach for identifying genes associated with prostate cancer progression and resistance to therapy. In our analysis, using a xenograft model of hormone refractory tumors, S100P was identified as a gene whose increased expression is associated with androgen independent growth of xenografts. Subsequent analysis of over 500 prostate specimens validated S100P as a protein whose overexpression is tightly associated with clinical prostate cancer progression suggesting that it may play a causal role in progression and...

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Expression array analysis of the hepatocyte growth factor invasive program

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Knockdown of S100P by lentiviral-mediated RNAi promotes apoptosis and suppresses the colony-formation ability of gastric cancer cells

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