Docetaxel induced-JNK2/PHD1 signaling pathway increases degradation of HIF-1α and causes cancer cell death under hypoxia

Abstract

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.

Brusatol-Mediated Inhibition of c-Myc Increases HIF-1α Degradation and Causes Cell Death in Colorectal Cancer under Hypoxia

“…As mentioned, HIF-1 is a major regulator protein in the tumor survival and progression, as well as chemoreisistance and radioresistance 13 . Therefore, HIF-1 has been regarded as an attractive target for cancer therapy over the past several years 6 , 13 .…”

“…It has been reported that, under hypoxia, HIFs are overexpressed in various cancer cells 7 , where they regulate the expression of a number of genes involved in angiogenesis, tumor growth, metastasis, metabolic reprogramming, chemoresistance, and radioresistance 7 - 12 . HIFs are heterodimeric transcription factors that consist of one of three oxygen-regulated α-subunits, HIF-1α, HIF-2α and HIF-3α, and a constitutively expressed hydrocarbon receptor/nuclear translocator β subunit, HIF-1β 7 , 13 - 17 . HIF-1 function requires formation of a HIF-1α/HIF-1β heterodimer, in which HIF-1α serves as the major regulatory subunit responsible for the transcriptional function of the complex 8 .…”

“…In hypoxic conditions, HIF-1α is not hydroxylated, preventing its interaction with pVHL and subsequent ubiquitination and proteasomal degradation 22 . Following hypoxia-induced stabilization, HIF-1α is translocated into the nucleus with HIF‑1β and binds to hypoxia-response elements (HREs), thereby increasing the transcription of approximately 100 genes involved in cellular adaptation and survival under hypoxic conditions 7 , 13 , 22 .…”

The PHD1 oxygen sensor in health and disease

“…Moreover, docetaxel‐caused apoptosis of cancer cells is at least partly mediated by activation of PHD1 and degradation of HIF1α (Oh et al . ). Similarly, PHD1 abundance is increased in breast cancer tissue after treatment with epirubicin and tamoxifen (Fox et al .…”

Hypoxia and Inflammation in Cancer, Focus on HIF and NF-кB

“…Conversely, treatment of breast cancer cell lines and a mouse xenograft model with docetaxel, a potential breast cancer drug, causes cell death in hypoxic conditions through c-Jun N-terminal Kinase 2 (JNK2)-PHD1 mediated HIF-1α degradation [173]. Interestingly, expression of individual PHD isoforms associates with good breast cancer patient outcome and PHD1 and PHD3 appear to be important in breast cancer in a HIF independent manner [174].…”