Abstract
Radiotherapy is the most successful nonsurgical treatment for nasopharyngeal carcinoma (NPC). Despite this, the prognosis remains poor. Although NPCs initially respond well to a full course of radiation, recurrence is frequent. The cancer stem cell (CSC) hypothesis provides a framework for explaining the discrepancy between the response of NPC to therapy and the poor survival rate. In this study, a stem cell-like subpopulation (PKH26+) was identified in NPC cell lines using a label-retention technique. PKH26+ cells were enriched for clonogenicity, sphere formation, side-population cells, and resistance to radiotherapy. Using genomic approaches, we show that the proto-oncogene c-MYC (MYC) regulates radiotolerance through transcriptional activation of CHK1 (CHEK1) and CHK2 (CHEK2) checkpoint kinases through direct binding to the CHK1 and CHK2 promoters. Overexpression of c-MYC in the PKH26+ subpopulation leads to increased expression of CHK1 and CHK2 and subsequent activation of the DNA-damage-checkpoint response, resulting in radioresistance. Furthermore, loss of CHK1 and CHK2 expression reverses radioresistance in PKH26+ (c-MYC high expression) cells in vitro and in vivo. This study elucidates the role of the c-MYC-CHK1/CHK2 axis in regulating DNA-damage-checkpoint responses and stem cell characteristics in the PKH26+ subpopulation. Furthermore, these data reveal a potential therapeutic application in reversal of radioresistance through inhibition of the c-MYC-CHK1/CHK2 pathway.
Highlights
Nasopharyngeal carcinoma (NPC) is a rare form of epithelial cancer that occurs in most parts of the world
Cell sorting and PKHþ cell characterization After labeling NPC cells with PKH26 and culturing for 30 days, we found that nondividing or slowly dividing cells remain brightly labeled with membrane intercalating dyes (Fig. 1A)
The results showed that mutated c-MYCc binding sites (c-MYCBS) did not display increased luciferase activity after c-MYC overexpression, confirming that c-MYC acts through CHK1 c-MYCBSs C and CHK2 c-MycBSs E (Fig. 4D)
Summary
Nasopharyngeal carcinoma (NPC) is a rare form of epithelial cancer that occurs in most parts of the world. Surgical approaches to treat NPC are limited by the inaccessibility of the anatomic location. NPC is sensitive to radiation and, treatments primarily rely on radiotherapy. Approximately 30% of patients presenting with localized tumors develop recurrent disease, and 30% to 60% of patients with metastatic NPC die within 5 years of diagnosis [2]. The concept of cancer stem cell (CSC) has been proposed, which is defined as a cell within a tumor that possesses the capacity to self-renew and to generate the Authors' Affiliations: 1Cancer Research Institute of Southern Medical University; and Departments of 2Radiation Oncology and 3Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, China
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
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.
