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

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 (PKH26þ) was identified in NPC cell lines using a label-retention technique. PKH26þ 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 PKH26þ 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 PKH26þ (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 PKH26þ subpopulation. Furthermore, these data reveal a potential therapeutic application in reversal of radioresistance through inhibition of the c-MYC-CHK1/CHK2 pathway. Cancer Res; 73(3); 1219-31. Ó2012 AACR.

IKKα-mediated biogenesis of miR-196a through interaction with Drosha regulates the sensitivity of cancer cells to radiotherapy

“…2,3 The mechanisms that cause NPC radiotherapy resistance are elusive. 4 IKKα is a subunit of IκB kinase (IKK) complex that consists of two highly homologous kinase subunits (IKKα and IKKβ) and a nonenzymatic regulatory component, IKKγ/NEMO. 5 Nuclear factor-κB (NF-κB) is generally activated through IKKdependent phosphorylation and subsequent degradation of IκB inhibitory proteins.…”

Transducin β-like 1 X-linked receptor 1 suppresses cisplatin sensitivity in Nasopharyngeal Carcinoma via activation of NF-κB pathway

“…Moverover, TBL1XR1 mRNA and protein expression are significantly correlated, suggeting that TBL1XR1 might be upregulated at the transcriptional level. By analysis of the promoter region of TBL1XR1 using the CONSITE program, we found two typical responsive E-BOX elements of transcriptional factor c-myc, which has been reported to be overexpressed in NPC [32]. Meanwhile, CpG islands were also observed in TBL1XR1 promoter.…”

E1a promotes c-Myc-dependent replicative stress

“…21 Furthermore, it's demonstrated that c-Myc controls Chk1 expression, at the transcriptional level. 29,52 Therefore, it seems to be plausible that c-Myc through RS (see below) would be implicated in the radiosensitivity associated to E1a. In this regard, it has been recently reported that c-Myc, through the transcriptional upregulation of Chk1/2, could be implicated in the radioresistant phenotype of cancer stem cell derived from nasopharyngeal carcinomas, 52 indicating that the effects of the c-Myc→Chk1 signaling axis could be dependent on the cell type (e.g., stem cell) or the genetic background (e.g., presence of E1a).…”