Antiangiogenic effects of ganetespib in colorectal cancer mediated through inhibition of HIF-1 alpha and STAT-3

作者：Ganji Purnachandra Nagaraju; Park Wungki; Wen Jing; Mahaseth Hemchandra; Landry Jerome; Farris Alton B; Willingham Field; Sullivan Patrick S; Proia David A; El Hariry Iman; Taliaferro Smith LaTonia; Diaz Roberto; El Rayes Bassel F^*

来源：Angiogenesis, 2013, 16(4): 903-917.

DOI：10.1007/s10456-013-9364-7

• HSP90
• HIF-1 alpha
• STAT-3
• Angiogenesis

Hypoxia-inducible factors (HIFs) and STAT-3 play essential roles in angiogenesis. HIF-1 alpha 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-1 alpha 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, TGF beta 1, VEGF, HIF-1 alpha and STAT-3 expression was observed in both cell lines treated ganetespib. HIF-1 alpha overexpression resulted in the increase VEGF and STAT-3 expression and this was inhibited by ganetespib. HIF-1 alpha knockdown inhibited VEGF and STAT-3 expression. STAT-3 knockdown inhibited VEGF but not HIF-1 alpha 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, TGF beta 1, VEGF, STAT-3 and HIF-1 alpha 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-1 alpha and STAT-3.

• 出版日期2013-10