title: Forkhead box M1 regulates quiescence-associated radioresistance of human head and neck squamous carcinoma cells.
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.
authors.affiliation: a  Free Radical and Radiation Biology Division, Department of Radiation Oncology.
authors.forename: Jaimee C
authors.initials: JC
authors.lastname: Eckers
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Kalen
authors.forename: Ehab H
authors.initials: EH
authors.lastname: Sarsour
authors.forename: Van S
authors.initials: VS
authors.lastname: Tompkins
authors.forename: Siegfried
authors.initials: S
authors.lastname: Janz
authors.forename: Jyung Mean
authors.initials: JM
authors.lastname: Son
authors.forename: Claire M
authors.initials: CM
authors.lastname: Doskey
authors.forename: Garry R
authors.initials: GR
authors.lastname: Buettner
authors.forename: Prabhat C
authors.initials: PC
authors.lastname: Goswami
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000528:radiation effects; D006258:Head and Neck Neoplasms / Q000473:pathology*; D006801:Humans; D010427:Pentose Phosphate Pathway / Q000187:drug effects / Q000528:radiation effects; D011836:Radiation Tolerance / Q000187:drug effects / Q000528:radiation effects*; D000077195:Squamous Cell Carcinoma of Head and Neck; D013883:Thiostrepton / Q000494:pharmacology
chemical_list: C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D013883:Thiostrepton