Abstract 547: The potential role of polo-like kinase 4 in non-melanoma skin cancers

Abstract

Abstract Nonmelanoma skin cancers (NMSC), including basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), are the most common malignancies in the United States, with over 5.4 million cases treated in more than 3.3 million people each year. The existing preventive and therapeutic strategies have not been fully effective in NMSC management. Therefore, an enhanced knowledge of the molecular mechanisms of NMSC may provide novel targets for prevention and treatment of these cancers. This study was undertaken to determine the potential role of the serine/threonine kinase, polo-like kinase 4 (PLK4) in NMSC. PLK4 plays an important role in cell division by regulating centriole duplication during the cell cycle. Essentially, PLK4 is a low abundance suicidal kinase capable of auto-phosphorylating itself to cause 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. In this study, employing in vitro and ex vivo approaches, we tested the hypothesis that PLK4 is differentially expressed in NMSC and may be used as a potential new target for the management of these neoplasms. Employing real time quantitative polymerase chain reaction as well as immunoblot analyses, we found that compared to normal human epidermal keratinocytes (NHEKs), PLK4 was significantly overexpressed in human epidermoid carcinoma A431 cells and basal cell carcinoma UW-BCC1 cell lines at both mRNA and protein levels. Further, we determined the expression profile of PLK4 in NMSC using immunohistochemical analysis of multiple tissue microarrays containing cores of normal skin, BCC and SCC. Our data demonstrated a marked overexpression of PLK4 in cancerous tissues, compared to normal skin. To further assess the role of PLK4 overexpression in NMSC, we determined the effects of small molecule inhibitors of PLK4, centrinone-B and CFI-400945 in vitro. We found that treatment with centrinone-B or CFI-400945 resulted in dose- as well as time-dependent decreases in the growth and viability. Further, centrinone-B and CFI-400945 treatments also resulted in a marked reduction in the clonogenic survival of skin cancer cells. Taken together, our study suggests that PLK4 has a pro-proliferative function in NMSC. Additional detailed studies are ongoing in our laboratory to determine the functional significance of PLK4 in NMSC. Based on our data, we suggest that PLK4 should be further evaluated as a potential target and prognostic biomarker for the management of NMSC. Citation Format: Debra R. Garvey, Mary A. Ndiaye, Chandra K. Singh, Ambria Noll, Nihal Ahmad. The potential role of polo-like kinase 4 in non-melanoma skin cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 547.