Characterization and Drug Response Analysis of a Newly Established Neuroendocrine Cervical Carcinoma Cell Line

• Main Authors: Lai, Zih-Yin, 賴姿吟
• Other Authors: Chuang, Yung-Jen
• Format: Others
• Language: en_US
• Published: 2017
• Online Access: http://ndltd.ncl.edu.tw/handle/wbs5vs

博士 === 國立清華大學 === 生物資訊與結構生物研究所 === 105 === Neuroendocrine cervical carcinoma (NECC) is a rare and aggressive subtype of cervical cancer. To date, no NECC cell-based model is available, which hinders the development of new therapeutic strategies for NECC. In this study, we derived a new NECC cell line from an ex vivo biopsy and used it to explore novel drug combination approach for NECC therapy. A NECC tissue sample from a 75-year-old female patient was processed to derive a primary cell line annotated as HM-1. The features of HM-1 in growth kinetics, biomarker profiles, and HPV exposure were analyzed to establish its characteristic profile. Next, HM-1 was treated with phosphatidylinositol-3 kinase (PI3K) inhibitors, BKM120 or BEZ235, or BEZ235 in combination with the two known genotoxic drugs, etoposide and/or cisplatin, that have been used in current NECC therapy, to evaluate which drug combination could serve as a more effective treatment approach. The inhibiting effects on HM-1 were evaluated by cell viability, apoptosis, and target kinase expression. The stable NECC cell line HM-1 displayed high expression levels of the neuroendocrine marker, synaptophysin. Human papillomavirus-16 was also found in HM-1 and HM-1 cell transplantation could induce tumor growth in nude mice. As expected, the combination of etoposide and cisplatin could synergistically inhibit HM-1 cell proliferation. Strikingly, when etoposide and cisplatin were combined with PI3K inhibitor BEZ235, the growth of HM-1 cells was significantly reduced. Kinase profiling revealed the expression levels of pAKT and p4E-BP1 were affected by BEZ235 treatment. Taken together, the data implied the combination of genotoxic drugs (etoposide and cisplatin) with BEZ235 not only inhibited HM-1 cell proliferation but also increased cell apoptosis. The newly established NECC cell line HM-1 could serve as a cell-based model for NECC research. The synergistic drug combination of PI3K inhibitor with genotoxic drugs might become a new treatment strategy against NECC.