Docetaxel-induced degradation of HIF-1α increases cancer cell death in hypoxic environment

초록

In the cancer treatment, the resistance of hypoxic cells to chemo- and radio-therapy is a major problem. HIF-1α has been shown to regulate 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, which has been approved by the FDA for treatment of various cancers, has been reported to enhance the degradation of HIF-1α, but its molecular mechanism is unclear. The purpose of this study was to examine the molecular mechanism underlying the docetaxel-induced degradation of HIF-1α and cell death in cancer cell under hypoxia.Under hypoxia, pharmacological inhibitors or siRNAs for PHD1 (prolyl hydroxylase 1) effectively prevented HIF-1α degradation and cancer cell death through inhibiting docetaxel-mediated activation of PHD1. In addition, siRNA-mediated knockdown of JNK2 blocked docetaxel-induced degradation of HIF-1α and cancer cell death through inhibiting the activation of PHD1. Through a luciferase reporter assay, we observed that the inhibition of the JNK2/PHD1 signaling pathway significantly suppressed the transcriptional activity of HIF-1α. Our results collectively show that, under hypoxia, docetaxel contributes to cause apoptotic cell death under hypoxia by triggering the JNK2/PHD1 signaling pathway, thereby increasing the degradation of HIF-1α. [This research was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (MRC: NRF-2014R1A5A2009392 and NRF-2013M2A2A7043703]