title: The different regulatory effects of p53 status on multidrug resistance are determined by autophagy in ovarian cancer cells.
abstract: OBJECTIVE
  Multidrug resistance (MDR) has become an obstacle for chemotherapy of cancer. p53 is reported to participate in the regulation of MDR, but the association between p53 status and MDR are complicated and conditional. It has been verified that apoptosis is not the only mechanism for MDR regulation by p53, the roles of autophagy in MDR is less studied.
  
  
  METHODS
  Human ovarian carcinoma cell lines SKOV3 and multidrug resistant phenotype SKVCR cells were used and wild-type p53 (wt p53) and mutant 175H constructs were introduced into cells to establish cell models with different p53 status by gene engineering, the sensitivity to vincristine (VCR), cisplatin (DDP), pirarubicin (THP) and etoposide (VP-16) were detected by MTT assay, Western blot and quantitative real-time PCR were used to detect the expression of protein and mRNA, especially, monodansylcadaverine (MDC) staining was used for autophagy rate, Hoechst 33342/propidium iodide (PI) were used to assess apoptosis and necrosis.
  
  
  RESULTS
  SKVCR cells induced by VCR shown overexpression of P-glycoprotein (P-gp) and MDR, and also displayed an enhanced autophagy compared with parental SKOV3. Wt p53 and 175H has no influence on drug sensitivity in SKOV3, while both sensitized SKVCR cells to VCR, THP and VP-16, especially 175H. The introduction of wt p53-induced apoptosis only, while 175H trigged autophagic cell death, necrosis and apoptosis so as to reverse the MDR.
  
  
  CONCLUSIONS
  The enhancement of autophagy in MDR cells allows to survive during chemotherapy stress, autophagy plays important role in wt p53 and mutant p53-immediated MDR. The different influence of p53 status on drug sensitivity hint the individual treatment strategies based on p53 status in patients.
authors.affiliation: Key Laboratory of Radiobiology-Ministry of Health, School of Public Health, Jilin University, 130021 Changchun, PR China.
authors.forename: Dejuan
authors.initials: D
authors.lastname: Kong
authors.forename: Shumei
authors.initials: S
authors.lastname: Ma
authors.forename: Bing
authors.initials: B
authors.lastname: Liang
authors.forename: Heqing
authors.initials: H
authors.lastname: Yi
authors.forename: Yinlong
authors.initials: Y
authors.lastname: Zhao
authors.forename: Rui
authors.initials: R
authors.lastname: Xin
authors.forename: Li
authors.initials: L
authors.lastname: Cui
authors.forename: Lili
authors.initials: L
authors.lastname: Jia
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Liu
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple; D005260:Female; D006801:Humans; D009154:Mutation; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics; D016133:Polymerase Chain Reaction; D015202:Protein Engineering; D012333:RNA, Messenger / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53