Interaction of heat shock protein 90 with hypoxia inducible factor and signal transducer and activator of transcription in colon cancer

Walid L. Shaib, Ganji Purnachandra Nagaraju, Batoul Farran, Gregory B. Lesinski, Bassel F. El-Rayes

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Hypoxia inducible factor (HIF)-1α and signal transducer and activator of transcription 3 (STAT-3) promote angiogenesis through transcriptional control of angiogenic cytokines such as vascular endothelial growth factor (VEGF). HIF-1α and STAT-3 represent clients of heat shock protein 90 (HSP90). We hypothesize that HSP90 inhibition can impair STAT-3 and HIF-1α activation, resulting in reduced VEGF expression in colorectal cancer (CRC). Protein levels and mRNA levels were measured using western blot and QRT-PCR, respectively, in CRC cell lines. Stable transfection and knockdown of HIF-1α, HSP90 and STAT-3 was performed in the two cell lines. Biologic effects following transfection were confirmed by chemical stimulation of STAT-3 with interleukin 6 (IL-6) and HIF-1α with hypoxia, respectively. HSP90 inhibition blocks the activation of its clients, HIF-1α and STAT-3, and inhibits VEGF transcription. HIF-1α is located downstream of HSP90 and the two molecules are co-dependent. Finally, STAT-3 inhibition affects VEGF expression only, thus disrupting angiogenesis. Inhibiting HSP90 is an effective approach to indirectly limit activity via HIF-1 α/STAT-3 and subsequent angiogenesis in CRC.

Original languageEnglish (US)
Pages (from-to)151-158
Number of pages8
JournalProcess Biochemistry
Volume86
DOIs
StatePublished - Nov 2019
Externally publishedYes

Keywords

  • Colorectal cancer
  • Heat shock protein 90
  • Hypoxia inducible factor-1α
  • Signal transducer and activator of transcription 3
  • Vascular endothelial growth factor

ASJC Scopus subject areas

  • Bioengineering
  • Biochemistry
  • Applied Microbiology and Biotechnology

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