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Forkhead box M1 regulates quiescence-associated radioresistance of human head and neck squamous carcinoma cells. Radiat Res 2014 Oct;182(4):420-9

Date

09/18/2014

Pubmed ID

25229973

Pubmed Central ID

PMC4221113

DOI

10.1667/RR13726.1

Scopus ID

2-s2.0-84922041422   13 Citations

Abstract

Cellular quiescence is a reversible growth arrest in which cells retain their ability to enter into and exit from the proliferative cycle. This study investigates the hypothesis that cell growth-state specific oxidative stress response regulates radiosensitivity of cancer cells. Results showed that quiescent (low proliferative index; >75% G1 phase and lower RNA content) Cal27 and FaDu human head and neck squamous cell carcinoma (HNSCC) are radioresistant compared to proliferating cells. Quiescent cells exhibited a three to tenfold increase in mRNA levels of Mn-superoxide dismutase (MnSOD), dual oxidase 2 (DUOX2) and dual-specificity phosphatase 1 (DUSP1), while mRNA levels of catalase (CAT), peroxiredoxin 3 (PRDX3) and C-C motif ligand 5 (CCL5) were approximately two to threefold lower compared to proliferating cells. mRNA levels of forkhead box M1 (FOXM1) showed the largest decrease in quiescent cells at approximately 18-fold. Surprisingly, radiation treatment resulted in a distinct gene expression pattern that is specific to proliferating and quiescent cells. Specifically, FOXM1 expression increased two to threefold in irradiated quiescent cells, while the same treatment had no net effect on FOXM1 mRNA expression in proliferating cells. RNA interference and pharmacological-based downregulation of FOXM1 abrogated radioresistance of quiescent cells. Furthermore, radioresistance of quiescent cells was associated with an increase in glucose consumption and expression of glucose-6-phosphate dehydrogenase (G6PD). Knockdown of FOXM1 resulted in a significant decrease in G6PD expression, and pharmacological-inhibition of G6PD sensitized quiescent cells to radiation. Taken together, these results suggest that targeting FOXM1 may overcome radioresistance of quiescent HNSCC.

Author List

Eckers JC, Kalen AL, Sarsour EH, Tompkins VS, Janz S, Son JM, Doskey CM, Buettner GR, Goswami PC

Author

Siegfried Janz MD Professor in the Medicine department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Carcinoma, Squamous Cell
Cell Cycle
Cell Line, Tumor
Cell Proliferation
Forkhead Box Protein M1
Forkhead Transcription Factors
Gene Expression Regulation, Neoplastic
Head and Neck Neoplasms
Humans
Pentose Phosphate Pathway
Radiation Tolerance
Thiostrepton