Docetaxel induced-JNK2/PHD1 signaling pathway increases degradation of HIF-1α and causes cancer cell death under hypoxia.
HIF-1 (hypoxia-inducible factor-1) regulates the expression of more than 70 genes involved in angiogenesis, tumor growth, metastasis, chemoresistance, and radioresistance. Thus, there is growing interest in using HIF-1 inhibitors as anticancer drugs. Docetaxel, a Food and Drug Administration-approved anticancer drug, is reported to enhance HIF-1α degradation. Here, we investigated the molecular mechanism underlying docetaxel-induced HIF-1α degradation and cancer cell death under hypoxic conditions. Docetaxel pretreatment enhanced the polyubiquitination and proteasome-mediated degradation of HIF-1α, and increased cancer cell death under hypoxic conditions. Docetaxel also activated the prolyl hydroxylase, PHD1, in hypoxia, and pharmacological inhibition or siRNA-mediated knockdown of PHD1 prevented docetaxel-induced HIF-1α degradation and cancer cell death. Additionally, siRNA-mediated JNK2 knockdown blocked docetaxel-induced HIF-1α degradation and cancer cell death by inhibiting PHD1 activation. A luciferase reporter assay revealed that inhibition of the JNK2/PHD1 signaling pathway significantly increased the transcriptional activity of HIF-1 in docetaxel-treated cancer cells under hypoxia. Consistent with these results, docetaxel-treated JNK2-knockdown tumors grew much faster than control tumors through inhibition of docetaxel-induced PHD1 activation and degradation of HIF-1α. Our results collectively show that, under hypoxic conditions, docetaxel induces apoptotic cell death through JNK2/PHD1 signaling-mediated HIF-1α degradation.
Department of Biomedical Sciences, College of Medicine, Inha University, Incheon 22212, Republic of Korea.|Hypoxia-related Disease Research Center, College of Medicine, Inha University, Incheon 22212, Republic of Korea.
Eun-Taex
ET
Oh
Department of Microbiology, College of Medicine, Inha University, Incheon 22212, Republic of Korea.
Chan Woo
CW
Kim
Department of Biomedical Sciences, College of Medicine, Inha University, Incheon 22212, Republic of Korea.
Soo Jung
SJ
Kim
Hypoxia-related Disease Research Center, College of Medicine, Inha University, Incheon 22212, Republic of Korea.|Department of Molecular Medicine, College of Medicine, Inha University, Incheon 22212, Republic of Korea.
Jae-Seon
JS
Lee
Department of Biomedical Sciences, College of Medicine, Inha University, Incheon 22212, Republic of Korea.|Hypoxia-related Disease Research Center, College of Medicine, Inha University, Incheon 22212, Republic of Korea.
Soon-Sun
SS
Hong
Hypoxia-related Disease Research Center, College of Medicine, Inha University, Incheon 22212, Republic of Korea.|Department of Microbiology, College of Medicine, Inha University, Incheon 22212, Republic of Korea.
Heon Joo
HJ
Park
D000595:Amino Acid Sequence; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D000077143:Docetaxel; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000737:chemistry / Q000378:metabolism*; D048056:Mitogen-Activated Protein Kinase 9 / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D059748:Proteolysis; D015398:Signal Transduction / Q000187:drug effects*; D043823:Taxoids / Q000494:pharmacology*; D054875:Ubiquitination
D000972:Antineoplastic Agents, Phytogenic; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D043823:Taxoids; D000077143:Docetaxel; C447780:EGLN2 protein, human; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D048056:Mitogen-Activated Protein Kinase 9