KNK437, abrogates hypoxia-induced radioresistance by dual targeting of the AKT and HIF-1α survival pathways

KNK437 is a benzylidene lactam compound known to inhibit stress-induced synthesis of heat shock proteins (HSPs). HSPs promote radioresistance and play a major role in stabilizing hypoxia inducible factor-1 alpha (HIF-1 alpha). HIF-1 alpha is widely responsible for tumor resistance to radiation under hypoxic conditions. We hypothesized that KNK437 sensitizes cancer cells to radiation and overrides hypoxia-induced radioresistance via destabilizing HIF-1 alpha. Treatment of human cancer cells MDA-MB-231 and T98G with KNK437 sensitized them to ionizing radiation (IR). Surprisingly, IR did not induce HSPs in these cell lines. As hypothesized, KNK437 abrogated the accumulation of HIF-1 alpha in hypoxic cells. However, there was no induction of HSPs under hypoxic conditions. Moreover, the proteosome inhibitor MG132 did not restore HIF-1 alpha levels in KNK437-treated cells. This suggested that the absence of HIF-1 alpha in hypoxic cells was not due to the enhanced protein degradation. HIF-1 alpha is mainly regulated at the level of post-transcription and ART is known to modulate the translation of HIF-1 alpha mRNA. Interestingly, pre-treatment of cells with KNK437 inhibited ART signaling. Furthermore, down regulation of ART by siRNA abrogated HIF-1 alpha levels under hypoxia. Interestingly, KNK437 reduced cell survival in hypoxic conditions and inhibited hypoxia-induced resistance to radiation. Taken together, these data suggest that KNK437 is an effective radiosensitizer that targets multiple pro-survival stress response pathways. (C) 2012 Elsevier Inc. All rights reserved.