Abstract LB-102: A pro-proliferative function of centriole duplication regulator, polo-like kinase-4 in human melanoma

Abstract

Abstract Malignant melanoma is one of the deadliest forms of skin cancer that remains resistant to existing therapeutic strategies. According to the SEER (Surveillance, Epidemiology, and End Results) program database of the National Cancer Institute, the 5-year survival rate for metastatic melanoma is a dismal 16%. Further, of the seven most common cancers in the USA, melanoma is the only neoplasm with constantly increasing incidence. Therefore, it is important to intensify our efforts to better-understand the genetics and biology of melanoma. This may lead to development of novel targets and biomarkers for management of this hard-to-treat neoplasm. This study was undertaken to determine the role and potential significance of polo-like kinase 4 (PLK4) in human melanoma. PLK4 is a serine/threonine kinase that has been shown to localize to centrioles and regulate centriole duplication during the cell cycle. While the potential role of PLK4 in cancer is beginning to be appreciated, there are evidence for its function as a tumor suppressor as well as tumor promoter. However, the role of PLK4 in melanoma is not known. Here, we employed in vitro and ex vivo experiments to determine the role of PLK4 in melanoma. Our data demonstrated that PLK4 was significantly overexpressed, both at mRNA and protein levels in human melanoma cells viz. A375, Hs294T, G361, 451Lu; when compared to the normal human epidermal melanocytes (NHEM). We also found a significant increase in PLK4 immunostaining in clinical melanoma tissues, compared to normal skin and nevus tissues. Further, treatment of melanoma cells with a selective small molecule PLK4 inhibitor, centrinone-B, was found to cause a significant decrease in the cell growth/viability and clonogenic survival in multiple melanoma cell lines. The observed anti-proliferative effects of centrinone-B were found to be accompanied with i) a G0/G1 phase arrest of cell cycle, and ii) induction of apoptosis, in human melanoma cells. Taken together, our study suggests a pro-proliferative role of PLK4 in human melanoma. Additional studies are ongoing in our laboratory to determine the functional significance of PLK4 in melanoma. We suggest that PLK4 should be further evaluated as a potential ‘druggable target’ and biomarker, for the management of melanoma. Citation Format: Maria Shabbir, Minakshi Nihal, Chandra K. Singh, B Jack Longley, Nihal Ahmad. A pro-proliferative function of centriole duplication regulator, polo-like kinase-4 in human melanoma. [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-102.