Interaction of heat shock protein 90 with hypoxia inducible factor and signal transducer and activator of transcription in colon cancer. (November 2019)

• Record Type: Journal Article
• Authors: Shaib, Walid L.; Nagaraju, Ganji Purnachandra; Farran, Batoul; Lesinski, Gregory B.; El-Rayes, Bassel F.
• Is Part Of: Process biochemistry. Volume 86(2019)
• Page Start: 151
• Page End: 158
• Publication Date: 2019-11
• Subjects: CRC colorectal cancer -- DFO deferoxamine -- EMT epithelial–mesenchymal transition -- EV empty vector -- GI gastrointestinal -- HIF-1α hypoxia inducible factor-1α -- IL-6 interleukin-6 -- KD knock-down -- OE overexpression -- PC pancreatic cancer -- PKD protein kinase D -- QRT-PCR quantitative reverse transcription polymerase chain reaction -- STAT-3 signal transducer and activator of transcription 3 -- SC scrambled vector -- TF transcription factor -- VEGF vascular endothelial growth factor -- VEGFR vascular endothelial growth factor receptor; Heat shock protein 90 -- Hypoxia inducible factor-1α -- Signal transducer and activator of transcription 3 -- Vascular endothelial growth factor -- Colorectal cancer; Biochemical engineering -- Periodicals; Biotechnology -- Periodicals; Biochemistry -- periodicals; Biotechnology -- periodicals; Chemical Engineering -- periodicals; Génie biochimique -- Périodiques; Biotechnologie -- Périodiques; Biochemical engineering; Biotechnology; Periodicals; 660.63
• DOI: 10.1016/j.procbio.2019.07.015
• Languages: English
• ISSNs: 1359-5113

Abstract

Graphical abstract: Highlights: Heat shock protein-90 (Hsp90) interacts with hypoxia inducible factor-1α (HIF1α). Hsp90 regulates HIF1α and signal transducer and activator of transcription 3 (STAT3). Hsp90 inhibition reduces HIF1α, STAT3 and vascular endothelial growth factor (VEGF). Hsp90 inhibition could be effective for colorectal cancer treatment. 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.