Abstract
Nasopharyngeal carcinoma is a rare but highly invasive cancer. As options of agents for effective combination chemoradiotherapy for advanced nasopharyngeal carcinoma are limited, novel therapeutic approaches are desperately needed. The ubiquitin ligase CHFR is known to target PARP1 for degradation and is epigenetically inactivated in nasopharyngeal carcinoma. We present evidence that PARP1 protein is indeed overexpressed in nasopharyngeal carcinoma cells in comparison with immortalized normal nasopharyngeal epithelial cells. Tissue microarray analysis also indicated that PARP1 protein is significantly elevated in primary nasopharyngeal carcinoma tissues, with strong correlation with all stages of nasopharyngeal carcinoma development. We found that the PARP inhibitor AZD2281 (olaparib) increased DNA damage, cell-cycle arrest, and apoptosis in nasopharyngeal carcinoma cells challenged with ionizing radiation or temozolomide. Isobologram analysis confirmed that the cytotoxicity triggered by AZD2281 and DNA-damaging agents was synergistic. Finally, AZD2281 also enhanced the tumor-inhibitory effects of ionizing radiation in animal xenograft models. These observations implicate that PARP1 overexpression is an early event in nasopharyngeal carcinoma development and provide a molecular basis of using PARP inhibitors to potentiate treatment of nasopharyngeal carcinoma with radio- and chemotherapy.
Highlights
Nasopharyngeal carcinoma is a highly invasive cancer
CHFR was found to be downregulated in all the nasopharyngeal carcinoma cell lines (Fig. 1A)
Given that PARP1 is overexpressed in nasopharyngeal carcinoma cells, we addressed whether this translates into alterations in the sensitivity to PARP inhibitors
Summary
Nasopharyngeal carcinoma is a highly invasive cancer. Nasopharyngeal carcinoma is relatively rare in most parts of the world (annual incidence rate generally less than 1 per 100,000 population), high incidence rates are found in southern China and Southeast Asia [1]. Nasopharyngeal carcinoma among women and men in Hong Kong is 7 and 18 per 100,000, respectively [2]. Authors' Affiliations: 1Division of Life Science, Center for Cancer Research, and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Clear Water Bay; 2Department of Pathology, Pamela Youde Nethersole Eastern Hospital; Departments of 3Pathology, 4Anatomy, and 5Clinical Oncology and Center for Cancer Research, The University of Hong Kong, Hong Kong. Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
