Beschreibung:
Abstract Prostate cancer (PCa) is the most prevalent non-cutaneous cancer of males. According to an estimate from the American Cancer Society, it is expected that approximately 180,890 new cases of PCa will be diagnosed and 26,120 PCa-related deaths will occur in the United States in 2016. Therefore, identification of additional molecular target(s) could be useful in designing novel mechanism-based approaches for the prevention and/or therapy of PCa. PLK4 belongs to the polo-like kinase family of serine/threonine protein kinases that localizes to centrioles and regulates centriole duplication during the cell cycle. Essentially, PLK4 is a low abundance suicidal kinase that is known to auto-phosphorylate itself to promote its own destruction to limit centriole duplication once per cell cycle phase. Since centrosome aberrations are frequently seen in cancer, the central role of PLK4 in centriole duplication suggests its significance as a potential target for cancer management. However, the role and functional relevance of PLK4 in PCa development and progression has not been investigated. In this study, we determined the expression profile of PLK4 in PCa using immunohistochemical analysis of multiple tissue microarrays (TMAs) containing a variety of cancerous and benign human prostate tissues. The TMAs were immunostained for PLK4 and the images were scanned and analyzed for protein levels using Aperio ScanScope at 40x magnification. We found a significant upregulation of PLK4 in PCa, compared to benign prostatic tissues. Further, we found a significant upregulation of PLK4 protein and mRNA in human PCa cells, as assessed by western blot and qRT-PCR analyses, respectively. To further assess the relevance of PLK4 overexpression in PCa, we determined the effect of a small molecule inhibitor of PLK4, centrinone-B, on androgen-responsive 22Rν1 and androgen-independent DU145 human PCa cells. Centrinone-B treatment (0, 50, 100 and 200 nM; for 24 and 48 h) resulted in a marked decrease in growth and viability of PCa cells, as assessed i) by CytoTox-Glo™ cytotoxicity assay, and ii) microscopic evaluation of cells following staining with Nuclear Fast Red and Crystal Violet dyes. Further, centrinone-B treatment resulted in a G1 phase cell cycle arrest of human PCa cells. Taken together, our study provides first direct evidence of a pro-proliferative function of PLK4 in PCa. However, additional studies are required to ascertain the relevance of our in vitro findings to in vivo situations in relevant animal models. Citation Format: Chandra K. Singh, Maria Shabbir, Minakshi Nihal, Kenneth A. Iczkowski, Nihal Ahmad. Polo-like kinase 4: A potential new target for the management of prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-228.