Docetaxel-induced activation of PHD1 Increases degradation of HIF-1a in hypoxic microenvironment

초록

HIF-1α, a major transcription factor of oxygen homeostasis, regulates the expression of more than 70 genes involved in angiogenesis, tumor growth, metastasis, chemoresistance and radioresistance. There has been a growing interest in using HIF-1α inhibitors as anticancer drugs. Recently, docetaxel has been reported to enhance the degradation of HIF-1α. The purpose of the present study was to elucidate the mechanism by which docetaxel downregulates HIF-1α expression leading to cancer cell death under hypoxic conditions. Under hypoxia, catalytic inhibitors or siRNAs for PHD1 effectively inhibited docetaxel-mediated HIF-1α degradation and cancer cell death through inhibiting the docetaxel-induced activation of PHD1. In addition, siRNA for JNK2 blocked docetaxel-induced degradation of HIF-1α and cancer cell death through inhibiting the activation of PHD1. Using a luciferase reporter assay, we observed that the inhibition of the JNK2/PHD1 signaling pathway significantly suppressed the transcriptional activity of HIF-1α. Collectively, we reveal that, under hypoxia, docetaxel causes apoptotic cell death under hypoxia by triggering the JNK2/PHD1 signaling pathway, thereby promoting the degradation of HIF-1α