C-terminal HSP90 Inhibitors Block the HSP90:HIF-1a Interaction and Inhibit the Cellular Hypoxic Response

Abstract

Hypoxia Inducible Factor (HIF) is a transcription factor activated by low oxygen, which is common in solid tumours. HIF controls the expression of genes involved in angiogenesis, chemotherapy resistance and metastasis. The chaperone HSP90 (Heat Shock Protein 90) stabilizes the subunit HIF-1 and prevents degradation. Previously identified HSP90 inhibitors bind to the N-terminal pocket of HSP90 which blocks binding to HIF-1, and produces HIF-1 degradation. N-terminal inhibitors have failed in the clinic as single therapy treatments due in part because they induce a heat shock response, which increases chemotherapy resistance. SM molecules are HSP90 inhibitors that bind to the C-terminus and do not activate the heat shock response. The effects of C-terminal HSP90 inhibitors on HIF-1 are unreported. Herein we show that SM compounds block binding between HSP90 and HIF-1, leading to HIF-1 degradation through the proteasome using the PHD/pVHL pathway in hypoxic conditions. The SM compounds decrease HIF-1 target gene expression at the mRNA and protein level under hypoxia in colorectal cancer cells, leading to cell death, without inducing a heat shock response. Our results suggest that targeting the C-terminus of HSP90 blocks the hypoxic response and may be an effective anti-cancer strategy.