title: The FOXM1-induced resistance to oxaliplatin is partially mediated by its novel target gene Mcl-1 in gastric cancer cells.
abstract: Myeloid cell leukemia-1 (Mcl-1) is an anti-apoptotic protein that belongs to the Bcl-2 family. The aberrant expression of Mcl-1 is important for sensitivity to chemotherapy drugs in gastric cancer. However, the regulatory mechanism of Mcl-1 in gastric cancer cells remains unclear. In this study, we first found that Forkhead box M1 (FOXM1) and Mcl-1 expression levels were positively correlated in human gastric cancer specimens and that both are associated with poor prognosis of patients treated with oxaliplatin. Second, we demonstrated that the expression level of Mcl-1 was correlated with FOXM1 expression in gastric cancer cells. Third, reporter assays showed that FOXM1 upregulated the promoter activity of the Mcl-1 gene. Electrophoretic mobility shift assays (EMSA) and chromatin immunoprecipitation (ChIP) assays further demonstrated that FOXM1 could bind to a particular site (-635acaaacaa-628) in the promoter region of the Mcl-1 gene. Moreover, CCK-8 assays and analyses of apoptosis revealed that the suppression of the FOXM1/Mcl-1 pathway induced apoptosis and thus increased sensitivity to oxaliplatin in gastric cancer cells, whereas the enhancement of the FOXM1/Mcl-1 pathway inhibited apoptosis and decreased sensitivity to oxaliplatin in gastric cancer cells. Taken together, this study is the first to not only show that Mcl-1 is a novel target gene of FOXM1 but also suggest that targeting FOXM1/Mcl-1 may be a novel strategy to enhance sensitivity to oxaliplatin in gastric cancer.
authors.affiliation: Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
authors.forename: Chang-Jiang
authors.initials: CJ
authors.lastname: Hu
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Tang
authors.affiliation: Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
authors.forename: Bai-jun
authors.initials: BJ
authors.lastname: Chen
authors.affiliation: Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
authors.forename: Yu-Feng
authors.initials: YF
authors.lastname: Xiao
authors.affiliation: Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Qin
authors.affiliation: Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Yong
authors.affiliation: Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Luo
authors.affiliation: Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
authors.forename: Jian-Wei
authors.initials: JW
authors.lastname: Zhang
authors.affiliation: Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, United States.
authors.forename: Song
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, China. Electronic address: hefengtian06@aliyun.com.
authors.forename: Fengtian
authors.initials: F
authors.lastname: He
authors.affiliation: Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China. Electronic address: shimingyang@yahoo.com.
authors.forename: Shi-Ming
authors.initials: SM
authors.lastname: Yang
mesh_terms: D000368:Aged; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000096:biosynthesis* / Q000235:genetics; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D011379:Prognosis; D011401:Promoter Regions, Genetic; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology
chemical_list: C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin
keywords: Apoptosis; FOXM1; Mcl-1; Oxaliplatin