title: FoxM1-mediated RFC5 expression promotes temozolomide resistance.
abstract: Although methylguanine-DNA-methyltransferase (MGMT) plays an important role in resistance to temozolomide (TMZ) in glioma, 40% of gliomas with MGMT inactivation are still resistant to TMZ. The underlying mechanism is not clear. Here, we report that forkhead box M1 (FoxM1) transcriptionally activates the expression of DNA repair gene replication factor C5 (RFC5) to promote TMZ resistance in glioma cells independent of MGMT activation. We showed that RFC5 expression is positively correlated with FoxM1 expression in human glioma cells and FoxM1 is able to transcriptionally activate RFC expression by interaction with the RFC5 promoter. Furthermore, knockdown of FoxM1 or RFC5 partially re-sensitizes glioma cells to TMZ. Consistently, thiostrepton, a FoxM1 inhibitor, in combination with TMZ significantly inhibits proliferation and promotes apoptosis in glioma cells. Taken together, these findings suggest that the FoxM1-RFC5 axis may mediate TMZ resistance and thiostrepton may serve as a potential therapeutic agent against TMZ resistance in glioma cells.
authors.affiliation: School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, China.
authors.forename: Wan-Xin
authors.initials: WX
authors.lastname: Peng
authors.affiliation: School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, China.
authors.forename: Xiu
authors.initials: X
authors.lastname: Han
authors.affiliation: School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, China.
authors.forename: Chun-Li
authors.initials: CL
authors.lastname: Zhang
authors.affiliation: Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, 212001, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Ge
authors.affiliation: School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, China.
authors.forename: Feng-Yi
authors.initials: FY
authors.lastname: Du
authors.affiliation: School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Jin
authors.affiliation: School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, China. ahg5@ujs.edu.cn.
authors.forename: Ai-Hua
authors.initials: AH
authors.lastname: Gong
mesh_terms: D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004260:DNA Repair; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D000072278:Forkhead Box Protein M1 / Q000235:genetics* / Q000378:metabolism; D005910:Glioma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051818:Replication Protein C / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D000077204:Temozolomide; D013883:Thiostrepton / Q000494:pharmacology
chemical_list: C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; C497564:RFC5 protein, human; D003606:Dacarbazine; D019853:O(6)-Methylguanine-DNA Methyltransferase; D051818:Replication Protein C; D013883:Thiostrepton; D000077204:Temozolomide
keywords: Chemo-resistance; FoxM1; Glioma; RFC5; TMZ