title: Synergistic roles of p53 and HIF1α in human renal cell carcinoma-cell apoptosis responding to the inhibition of mTOR and MDM2 signaling pathways.
abstract: BACKGROUND
  mTOR and MDM2 signaling pathways are frequently deregulated in cancer development, and inhibition of mTOR or MDM2 independently enhances carcinoma-cell apoptosis. However, responses to mTOR and MDM2 antagonists in renal cell carcinoma (RCC) remain unknown.
  
  
  METHODS
  A498 cells treated with MDM2 antagonist MI-319 and/or mTOR inhibitor rapamycin were employed in the present study. Cell apoptosis and Western blot analysis were performed.
  
  
  CONCLUSIONS
  We found that the MDM2 inhibitor MI-319 induced RCC cell apoptosis mainly dependent on p53 overexpression, while the mTOR antagonist rapamycin promoted RCC cell apoptosis primarily through upregulation of HIF1α expression. Importantly, strong synergistic effects of MI-319 and rapamycin combinations at relatively low concentrations on RCC cell apoptosis were observed. Depletion of p53 or HIF1α impaired both antagonist-elicited apoptoses to differential extents, corresponding to their expression changes responding to chemical treatments, and double knockdown of p53 and HIF1α remarkably hindered MI-319- or rapamycin-induced apoptosis, suggesting that both p53 and HIF1α are involved in MDM2 or mTOR antagonist-induced apoptosis. Collectively, we propose that concurrent activation of p53 and HIF1α may effectively result in cancer-cell apoptosis, and that combined MDM2 antagonists and mTOR inhibitors may be useful in RCC therapy.
authors.affiliation: Department of Urology Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, People's Republic of China.
authors.forename: Qing-jun
authors.initials: QJ
authors.lastname: Liu
authors.affiliation: Department of Urology Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, People's Republic of China.
authors.forename: Hong-liang
authors.initials: HL
authors.lastname: Shen
authors.affiliation: Department of Urology Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, People's Republic of China.
authors.forename: Jun
authors.initials: J
authors.lastname: Lin
authors.affiliation: Department of Urology Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, People's Republic of China.
authors.forename: Xiu-hong
authors.initials: XH
authors.lastname: Xu
authors.affiliation: Department of Urology Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, People's Republic of China.
authors.forename: Zheng-guo
authors.initials: ZG
authors.lastname: Ji
authors.affiliation: Department of Urology Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, People's Republic of China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Han
authors.affiliation: Department of Urology Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, People's Republic of China.
authors.forename: Dong-hao
authors.initials: DH
authors.lastname: Shang
authors.affiliation: Department of Urology Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, People's Republic of China.
authors.forename: Pei-qian
authors.initials: PQ
authors.lastname: Yang
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013141:Spiro Compounds / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007211:Indoles; C548961:MI 319; D047428:Protein Kinase Inhibitors; D013141:Spiro Compounds; D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2; D058570:TOR Serine-Threonine Kinases
keywords: HIF1α; MDM2; apoptosis; mTOR; p53; renal cell carcinoma