Taxol-induced unfolded protein response activation in breast cancer cells exposed to hypoxia: ATF4 activation regulates autophagy and inhibits apoptosis

Notte, Annick; Rebucci, Magali; Fransolet, Maude; Roegiers, Edith; Genin, Marie; Tellier, Céline; Watillon, Kassandra; Fattaccioli, Antoine; Arnould, Thierry; Michiels, Carine

doi:10.1016/j.biocel.2015.02.010

Cited by 55 publications

(36 citation statements)

References 71 publications

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“…S2). Previous studies have reported that hypoxia-induced autophagy promotes paclitaxel resistance in cancer cells3839. We found that the autophagy markers, Beclin-1 and LC3-I/II, were increased in paclitaxel-treated cancer cells, but not in docetaxel-treated cancer cells (Fig.…”

Section: Discussionmentioning

confidence: 49%

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

Kim

et al. 2016

Sci Rep

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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.

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Section: Discussionmentioning

confidence: 49%

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

Kim

et al. 2016

Sci Rep

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“…These findings may each explain cytoprotection by TERS, independent of Wnt signaling. Concordantly, the PERK pathway and its downstream effector ATF4 have been implicated in prosurvival signaling during nutrient deprivation (52, 53) and bortezomib (31) and paclitaxel (54) cytotoxicities. We therefore hypothesized that the PERK pathway is central to the facilitation of TERS-induced cytoprotection.…”

Section: Resultsmentioning

confidence: 99%

Intercellular transmission of the unfolded protein response promotes survival and drug resistance in cancer cells

et al. 2017

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Increased protein translation in cells and various factors in the tumor microenvironment can induce endoplasmic reticulum (ER) stress, which initiates the unfolded protein response (UPR). We have previously reported that factors released from cancer cells mounting a UPR induce a de novo UPR in bone marrow–derived myeloid cells, macrophages, and dendritic cells that facilitates protumorigenic characteristics in culture and tumor growth in vivo. We investigated whether this intercellular signaling, which we have termed transmissible ER stress (TERS), also operates between cancer cells and what its functional consequences were within the tumor. We found that TERS signaling induced a UPR in recipient human prostate cancer cells that included the cell surface expression of the chaperone GRP78. TERS also activated Wnt signaling in recipient cancer cells and enhanced resistance to nutrient starvation and common chemotherapies such as the proteasome inhibitor bortezomib and the microtubule inhibitor paclitaxel. TERS-induced activation of Wnt signaling required the UPR kinase and endonuclease IRE1. However, TERS-induced enhancement of cell survival was predominantly mediated by the UPR kinase PERK and a reduction in the abundance of the transcription factor ATF4, which prevented the activation of the transcription factor CHOP and, consequently, the induction of apoptosis. When implanted in mice, TERS-primed cancer cells gave rise to faster growing tumors than did vehicle-primed cancer cells. Collectively, our data demonstrate that TERS is a mechanism of intercellular communication through which tumor cells can adapt to stressful environments.

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“…EnR stress occurs in response to nutrient deprivation, hypoxia, and alterations in protein glycosylation, resulting in accumulation of unfolded and/or misfolded proteins in the EnR lumen (19,20). The unfolded protein response (UPR) is one of the cellular defense mechanisms triggered in response to chemotherapy (35,36,54). HIF1a hypoxiarelated response has also been described as a possible mechanism of resistance activated by chemotherapy (40,54).…”

Section: Discussionmentioning

confidence: 99%

“…Taxane-derived therapies have been linked to activation of the EnR stress response (35,36). To investigate whether interactions between the NOS inhibitor L-NMMA and chemotherapy may have altered this pathway, Western blot analyses of SUM-159PT and MDA-MB 436 cell lysates were performed.…”

Section: Nos Blockade Enhances Docetaxel-induced Apoptosis By Augmentmentioning

confidence: 99%

Pharmacological Inhibition of NOS Activates ASK1/JNK Pathway Augmenting Docetaxel-Mediated Apoptosis in Triple-Negative Breast Cancer

Dávila‐González

Choi

Rosato

et al. 2018

Clinical Cancer Research

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Purpose: Chemoresistance in triple-negative breast cancer (TNBC) is associated with the activation of a survival mechanism orchestrated by the endoplasmic reticulum (EnR) stress response and by inducible nitric oxide synthase (iNOS). Our aim was to determine the effects of pharmacologic NOS inhibition on TNBC.Experimental Design: TNBC cell lines, SUM-159PT, MDA-MB-436, and MDA-MB-468, were treated with docetaxel and NOS inhibitor (L-NMMA) for 24, 48, and 72 hours. Apoptosis was assessed by flow cytometry using Annexin-V and propidium iodide. Western blot was used to assess ER stress and apoptosis, and rtPCR was used to evaluate s-XBP1. TNBC patient-derived xenografts (PDX) were treated either with vehicle, docetaxel, or combination therapy (NOS inhibition þ docetaxel). Mouse weight and tumor volumes were recorded twice weekly. Docetaxel concentration was determined using mass spectrometry. To quantify proliferation and apoptosis, PDX tumor samples were stained using Ki67 and TUNEL assay.Results: In vitro, L-NMMA ameliorated the iNOS upregulation associated with docetaxel. Apoptosis increased when TNBC cells were treated with combination therapy. In TNBC PDXs, combination therapy significantly reduced tumor volume growth and increased survival proportions. In the BCM-5998 PDX model, intratumoral docetaxel concentration was higher in mice receiving combination therapy. Coupling docetaxel with NOS inhibition increased EnR-stress response via coactivation of ATF4 and CHOP, which triggered the pASK1/JNK proapoptotic pathway, promoting cleavage of caspases 3 and 9.Conclusions: iNOS is a critical target for docetaxel resistance in TNBC. Pharmacologic inhibition of NOS enhanced chemotherapy response in TNBC PDX models. Combination therapy may improve prognosis and prevent relapse in TNBC patients who have failed conventional chemotherapy.

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Taxol-induced unfolded protein response activation in breast cancer cells exposed to hypoxia: ATF4 activation regulates autophagy and inhibits apoptosis

Cited by 55 publications

References 71 publications

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

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

Intercellular transmission of the unfolded protein response promotes survival and drug resistance in cancer cells

Pharmacological Inhibition of NOS Activates ASK1/JNK Pathway Augmenting Docetaxel-Mediated Apoptosis in Triple-Negative Breast Cancer

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