title: Antiangiogenic effects of ganetespib in colorectal cancer mediated through inhibition of HIF-1α and STAT-3.
abstract: Hypoxia-inducible factors (HIFs) and STAT-3 play essential roles in angiogenesis. HIF-1α and STAT-3 are clients of the heat shock protein 90 (HSP90). We hypothesized that ganetespib, a potent HSP90 inhibitor, would disrupt angiogenesis in colorectal cancer (CRC) through inhibition of HIF-1α and STAT-3. CRC cell lines (HCT116 and HT29) were used in all the experiments. Egg CAM and HUVEC assays revealed decreased angiogenesis in ganetespib treated cell lines. Ganetespib inhibited matrigel plug vascularization and tumor growth of xenografts. Significant inhibition of PDGFA, FGF2, Ang-1, Ang-2, TGFβ1, VEGF, HIF-1α and STAT-3 expression was observed in both cell lines treated ganetespib. HIF-1α overexpression resulted in the increase VEGF and STAT-3 expression and this was inhibited by ganetespib. HIF-1α knockdown inhibited VEGF and STAT-3 expression. STAT-3 knockdown inhibited VEGF but not HIF-1α expression. HSP90, STAT-3 and VEGF expression was significantly higher in CRC compared to adjacent normal tissue. Significant downregulation of PDGFA, FGF2, Ang-1, Ang-2, TGFβ1, VEGF, STAT-3 and HIF-1α mRNA was observed in the post ganetespib treatment tumor samples from patients with rectal cancer. These results collectively suggest that inhibition of HSP90 is a promising antiangiogenic strategy in CRC. HSP90 angiogenic effects are mediated through HIF-1α and STAT-3.
authors.affiliation: Department of Hematology and Medical Oncology, Emory University, 1365 Clifton RD NE, Office 2080, Atlanta, GA, 30322, USA.
authors.forename: Ganji Purnachandra
authors.initials: GP
authors.lastname: Nagaraju
authors.affiliation: Department of Hematology and Medical Oncology, Emory University, 1365 Clifton RD NE, Office 2080, Atlanta, GA, 30322, USA.
authors.forename: Purnachandra Nagaraju
authors.initials: PN
authors.lastname: Ganji
authors.forename: Wungki
authors.initials: W
authors.lastname: Park
authors.forename: Jing
authors.initials: J
authors.lastname: Wen
authors.forename: Hemchandra
authors.initials: H
authors.lastname: Mahaseth
authors.forename: Jerome
authors.initials: J
authors.lastname: Landry
authors.forename: Alton B
authors.initials: AB
authors.lastname: Farris
authors.forename: Field
authors.initials: F
authors.lastname: Willingham
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Sullivan
authors.forename: David A
authors.initials: DA
authors.lastname: Proia
authors.forename: Iman
authors.initials: I
authors.lastname: El-Hariry
authors.forename: Latonia
authors.initials: L
authors.lastname: Taliaferro-Smith
authors.forename: Roberto
authors.initials: R
authors.lastname: Diaz
authors.forename: Bassel F
authors.initials: BF
authors.lastname: El-Rayes
mesh_terms: D000230:Adenocarcinoma / Q000098:blood supply* / Q000188:drug therapy / Q000473:pathology; D020533:Angiogenesis Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000098:blood supply; D003094:Collagen; D015179:Colorectal Neoplasms / Q000098:blood supply* / Q000473:pathology; D015536:Down-Regulation; D004338:Drug Combinations; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D007797:Laminin; D008819:Mice, Nude; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D011509:Proteoglycans; D012333:RNA, Messenger / Q000096:biosynthesis; D012004:Rectal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D012259:Ribonuclease, Pancreatic / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D013047:Specific Pathogen-Free Organisms; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D014230:Triazoles / Q000494:pharmacology* / Q000627:therapeutic use; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D033921:Vesicular Transport Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D004338:Drug Combinations; C497442:HIF1A protein, human; D018841:HSP90 Heat-Shock Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007797:Laminin; D010982:Platelet-Derived Growth Factor; D011509:Proteoglycans; D012333:RNA, Messenger; C533237:STA 9090; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; D014230:Triazoles; C467484:VEGFA protein, human; C555023:VPS51 protein, human; D042461:Vascular Endothelial Growth Factor A; D033921:Vesicular Transport Proteins; C075278:platelet-derived growth factor A; D016222:Fibroblast Growth Factor 2; C059485:matrigel; D003094:Collagen; C046366:angiogenin; D012259:Ribonuclease, Pancreatic