title: Resveratrol protects leukemic cells against cytotoxicity induced by proteasome inhibitors via induction of FOXO1 and p27Kip1.
abstract: BACKGROUND
  It was reported recently that resveratrol could sensitize a number of cancer cells to the antitumoral effects of some conventional chemotherapy drugs. The current study was designed to investigate whether resveratrol could sensitize leukemic cells to proteasome inhibitors.
  
  
  METHODS
  Leukemic cells were treated with MG132 alone or in combination with resveratrol. Cell viability was investigated using MTT assay, and induction of apoptosis and cell cycle distribution was measured using flow cytometry. Western blot and real-time RT-PCR were used to investigate the expression of FOXO1 and p27Kip1. CHIP was performed to investigate the binding of FOXO1 to the p27 Kip1 promoter.
  
  
  RESULTS
  Resveratrol strongly reduced cytotoxic activities of proteasome inhibitors against leukemic cells. MG132 in combination with resveratrol caused cell cycle blockade at G1/S transition via p27Kip1 accumulation. Knockdown of p27Kip1 using siRNA dramatically attenuated the protective effects of resveratrol on cytotoxic actions of proteasome inhibitors against leukemic cells. Resveratrol induced FOXO1 expression at the transcriptional level, while MG132 increased nuclear distribution of FOXO1. MG132 in combination with resveratrol caused synergistic induction of p27Kip1 through increased recruitment of FOXO1 on the p27Kip1 promoter.
  
  
  CONCLUSIONS
  Resveratrol may have the potential to negate the cytotoxic effects of proteasome inhibitors via regulation of FOXO1 transcriptional activity and accumulation of p27Kip1.
authors.affiliation: Department of Biochemistry & Molecular Biology, China Medical University, Shenyang 110001, PR China.
authors.forename: Xiao-Fang
authors.initials: XF
authors.lastname: Niu
authors.forename: Bao-Qin
authors.initials: BQ
authors.lastname: Liu
authors.forename: Zhen-Xian
authors.initials: ZX
authors.lastname: Du
authors.forename: Yan-Yan
authors.initials: YY
authors.lastname: Gao
authors.forename: Chao
authors.initials: C
authors.lastname: Li
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.forename: Yifu
authors.initials: Y
authors.lastname: Guan
authors.forename: Hua-Qin
authors.initials: HQ
authors.lastname: Wang
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D045744:Cell Line, Tumor; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics* / Q000502:physiology; D019610:Cytoprotection / Q000187:drug effects / Q000235:genetics; D003603:Cytotoxins / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000502:physiology; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D020014:K562 Cells; D007938:Leukemia / Q000235:genetics / Q000473:pathology*; D061988:Proteasome Inhibitors; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D020298:U937 Cells
chemical_list: D003603:Cytotoxins; D004791:Enzyme Inhibitors; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D061988:Proteasome Inhibitors; D013267:Stilbenes; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000077185:Resveratrol