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

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An Erratum to this article was published on 02 August 2013

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.

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Acknowledgments

B. El-Rayes and R. Diaz receive research support from Synta Pharmaceuticals. This work was supported by Georgia Cancer Coalition (#00026700), Kennedy Award (#00015855).

Conflict of interest

None.

Ethical standards

The experiments comply with the current laws of the United States of America. Cancer.gov number: NCT 01554969.

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Authors and Affiliations

  1. Department of Hematology and Medical Oncology, Emory University, 1365 Clifton RD NE, Office 2080, Atlanta, GA, 30322, USA

    Purnachandra Nagaraju Ganji, Hemchandra Mahaseth, LaTonia Taliaferro-Smith & Bassel F. El-Rayes

  2. Department of Radiation Oncology, Emory University, Atlanta, GA, 30322, USA

    Wungki Park, Jing Wen, Jerome Landry & Roberto Diaz

  3. Department of Pathology, Emory University, Atlanta, GA, 30322, USA

    Alton B. Farris

  4. Department of Medicine, Division of Gastroenterology, Emory University, Atlanta, GA, 30322, USA

    Field Willingham

  5. Department of Surgery Division of Surgical Oncology, Emory University, Atlanta, GA, 30322, USA

    Patrick S. Sullivan

  6. Synta Pharmaceuticals Corporation, Lexington, MA, USA

    David A. Proia & Iman El-Hariry

Authors
  1. Purnachandra Nagaraju Ganji
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  2. Wungki Park
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  10. Iman El-Hariry
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  11. LaTonia Taliaferro-Smith
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  12. Roberto Diaz
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  13. Bassel F. El-Rayes
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Corresponding author

Correspondence to Bassel F. El-Rayes.

Additional information

Roberto Diaz and Bassel F. El-Rayes have equally contributed to this work.

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Ganji, P.N., Park, W., Wen, J. et al. Antiangiogenic effects of ganetespib in colorectal cancer mediated through inhibition of HIF-1α and STAT-3. Angiogenesis 16, 903–917 (2013). https://doi.org/10.1007/s10456-013-9364-7

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  • DOI: https://doi.org/10.1007/s10456-013-9364-7

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