title: Hedgehog signaling antagonist GDC-0449 (Vismodegib) inhibits pancreatic cancer stem cell characteristics: molecular mechanisms.
abstract: BACKGROUND
  Recent evidence from in vitro and in vivo studies has demonstrated that aberrant reactivation of the Sonic Hedgehog (SHH) signaling pathway regulates genes that promote cellular proliferation in various human cancer stem cells (CSCs). Therefore, the chemotherapeutic agents that inhibit activation of Gli transcription factors have emerged as promising novel therapeutic drugs for pancreatic cancer. GDC-0449 (Vismodegib), orally administrable molecule belonging to the 2-arylpyridine class, inhibits SHH signaling pathway by blocking the activities of Smoothened. The objectives of this study were to examine the molecular mechanisms by which GDC-0449 regulates human pancreatic CSC characteristics in vitro.
  
  
  RESULTS
  GDC-0499 inhibited cell viability and induced apoptosis in three pancreatic cancer cell lines and pancreatic CSCs. This inhibitor also suppressed cell viability, Gli-DNA binding and transcriptional activities, and induced apoptosis through caspase-3 activation and PARP cleavage in pancreatic CSCs. GDC-0449-induced apoptosis in CSCs showed increased Fas expression and decreased expression of PDGFRα. Furthermore, Bcl-2 was down-regulated whereas TRAIL-R1/DR4 and TRAIL-R2/DR5 expression was increased following the treatment of CSCs with GDC-0449. Suppression of both Gli1 plus Gli2 by shRNA mimicked the changes in cell viability, spheroid formation, apoptosis and gene expression observed in GDC-0449-treated pancreatic CSCs. Thus, activated Gli genes repress DRs and Fas expressions, up-regulate the expressions of Bcl-2 and PDGFRα and facilitate cell survival.
  
  
  CONCLUSIONS
  These data suggest that GDC-0499 can be used for the management of pancreatic cancer by targeting pancreatic CSCs.
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, and Medicine, The University of Kansas Medical Center, Kansas City, Kansas, United States of America.
authors.forename: Brahma N
authors.initials: BN
authors.lastname: Singh
authors.forename: Junsheng
authors.initials: J
authors.lastname: Fu
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Srivastava
authors.forename: Sharmila
authors.initials: S
authors.lastname: Shankar
mesh_terms: D000813:Anilides / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000473:pathology*; D011725:Pyridines / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled; D015398:Signal Transduction; D000072086:Smoothened Receptor; D014157:Transcription Factors / Q000187:drug effects
chemical_list: D000813:Anilides; D053823:Hedgehog Proteins; C538724:HhAntag691; D011725:Pyridines; D043562:Receptors, G-Protein-Coupled; C491023:SMO protein, human; D000072086:Smoothened Receptor; D014157:Transcription Factors
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