MYC Regulation of CHK1 and CHK2 Promotes Radioresistance in a Stem Cell-like Population of Nasopharyngeal Carcinoma Cells

• Published in: Cancer research (Chicago, Ill.) Vol. 73; no. 3; pp. 1219 - 1231
• Main Authors: WANG, Wen-Jun, WU, Si-Pei, LIU, Jia-Bin, SHI, Yong-Sheng, XUE HUANG, ZHANG, Qian-Bing, YAO, Kai-Tai
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-02-2013
• Subjects: Animals; Biological and medical sciences; Carcinoma; Cell Line, Tumor; Checkpoint Kinase 1; Checkpoint Kinase 2; DNA Damage; DNA Repair; Female; Humans; Medical sciences; Mice; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms - pathology; Nasopharyngeal Neoplasms - radiotherapy; Neoplastic Stem Cells - radiation effects; Organic Chemicals - analysis; Otorhinolaryngology. Stomatology; Protein Kinases - physiology; Protein-Serine-Threonine Kinases - physiology; Proto-Oncogene Proteins c-myc - physiology; Radiation Tolerance; Treatment with physical agents; Treatment. General aspects; Tumors; Upper respiratory tract, upper alimentary tract, paranasal sinuses, salivary glands: diseases, semeiology; Human; Treatment resistance; Nasopharynx cancer; Stem cell; Malignant tumor; Nasopharynx carcinoma; Radiotherapy; In vitro; Serine/threonine-protein kinase Chk2; Treatment; Serine/threonine-protein kinase Chk1; Cell population; Animal; C-Onc gene; myc Gene; ENT disease; Pharynx disease; Protooncogene; Cancer
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-12-1408

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.