title: PDGF upregulates Mcl-1 through activation of β-catenin and HIF-1α-dependent signaling in human prostate cancer cells.
abstract: BACKGROUND
  Aberrant platelet derived growth factor (PDGF) signaling has been associated with prostate cancer (PCa) progression. However, its role in the regulation of PCa cell growth and survival has not been well characterized.
  
  
  RESULTS
  Using experimental models that closely mimic clinical pathophysiology of PCa progression, we demonstrated that PDGF is a survival factor in PCa cells through upregulation of myeloid cell leukemia-1 (Mcl-1). PDGF treatment induced rapid nuclear translocation of β-catenin, presumably mediated by c-Abl and p68 signaling. Intriguingly, PDGF promoted formation of a nuclear transcriptional complex consisting of β-catenin and hypoxia-inducible factor (HIF)-1α, and its binding to Mcl-1 promoter. Deletion of a putative hypoxia response element (HRE) within the Mcl-1 promoter attenuated PDGF effects on Mcl-1 expression. Blockade of PDGF receptor (PDGFR) signaling with a pharmacological inhibitor AG-17 abrogated PDGF induction of Mcl-1, and induced apoptosis in metastatic PCa cells.
  
  
  CONCLUSIONS
  Our study elucidated a crucial survival mechanism in PCa cells, indicating that interruption of the PDGF-Mcl-1 survival signal may provide a novel strategy for treating PCa metastasis.
authors.affiliation: Department of Urology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Shareen
authors.initials: S
authors.lastname: Iqbal
authors.forename: Shumin
authors.initials: S
authors.lastname: Zhang
authors.forename: Adel
authors.initials: A
authors.lastname: Driss
authors.forename: Zhi-Ren
authors.initials: ZR
authors.lastname: Liu
authors.forename: Hyeong-Reh Choi
authors.initials: HR
authors.lastname: Kim
authors.forename: Yanru
authors.initials: Y
authors.lastname: Wang
authors.forename: Chad
authors.initials: C
authors.lastname: Ritenour
authors.forename: Haiyen E
authors.initials: HE
authors.lastname: Zhau
authors.forename: Omer
authors.initials: O
authors.lastname: Kucuk
authors.forename: Leland W K
authors.initials: LW
authors.lastname: Chung
authors.forename: Daqing
authors.initials: D
authors.lastname: Wu
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008297:Male; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010982:Platelet-Derived Growth Factor; D019253:Proto-Oncogene Proteins c-bcl-2; D051176:beta Catenin