STAT3 and HIF1α cooperatively activate HIF1 target genes in MDA-MB-231 and RCC4 cells

Pawlus, Matthew R.; Wang, L; Hu, Cheng-Jun

doi:10.1038/onc.2013.115

Cited by 194 publications

(188 citation statements)

References 62 publications

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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%

“…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). Human melanoma cells under EnR stress acquire resistance to microtubuletargeting drugs through XBP-1-mediated activation of Akt (55).…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

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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“…TRPC1 is a regulator of hypoxia-induced EGFR and STAT3 activation EGFR and STAT3 signalling are two key hypoxia-associated signalling pathways (Selvendiran et al, 2009;Pawlus et al, 2014;Peng et al, 2006) that also have important roles in EMT induced by hypoxia (Cui et al, 2016;Misra et al, 2012) and EGF (Lo et al, 2007), although their potential regulation by TRPC1 is unknown. We assessed EGFR at Y1173 (an important site of EGFR autophosphorylation; Kondratov et al, 2010) and STAT3 phosphorylation at Y705 in MDA-MB-468 cells under hypoxic conditions for 6, 24 and 48 h. Phosphorylation of EGFR was significantly enhanced after 24 and 48 h of hypoxia, with no significant concomitant change in total EGFR protein ( Fig.…”

Section: Trpc1 Expression Is Increased During Hypoxia and Is Requiredmentioning

confidence: 99%

TRPC1 is a differential regulator of hypoxia-mediated events and Akt signaling in PTEN-deficient breast cancer cells

Azimi

Milevskiy

Kaemmerer

et al. 2017

Journal of Cell Science

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Hypoxia is a feature of the tumour microenvironment that promotes invasiveness, resistance to chemotherapeutics and cell survival. Our studies identify the transient receptor potential canonical-1 (TRPC1) ion channel as a key component of responses to hypoxia in breast cancer cells. This regulation includes control of specific epithelial to mesenchymal transition (EMT) events and hypoxia-mediated activation of signalling pathways such as activation of the EGFR, STAT3 and the autophagy marker LC3B, through hypoxia-inducible factor-1α (HIF1α)-dependent and -independent mechanisms. TRPC1 regulated HIF1α levels in PTEN-deficient MDA-MB-468 and HCC1569 breast cancer cell lines. This regulation arises from effects on the constitutive translation of HIF1α under normoxic conditions via an Akt-dependent pathway. In further support of the role of TRPC1 in EMT, its expression is closely associated with EMT-and metastasisrelated genes in breast tumours, and is enhanced in basal B breast cancer cell lines. TRPC1 expression is also significantly prognostic for basal breast cancers, particularly those classified as lymph node positive. The defined roles of TRPC1 identified here could be therapeutically exploited for the control of oncogenic pathways in breast cancer cells.

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“…Individual TFs in the enhanceosome complex may promote transcription by recruiting RNA polymerase II/general TFs and/or by recruiting chromatin-modifying enzymes such as histone acetylase, CBP and p300, and the chromatin-remodeling SWI/SNF complex. In the context of the enhanceosome associated with the Hx response, two additional TFs, STAT3 and USF2, are required for maximal Hx response (11,12). STAT3 and USF2 function in the Hx response by recruiting CBP and p300 to the HIF1 and HIF2 target genes, respectively (11,12).…”

mentioning

confidence: 99%

BRG1 and BRM Chromatin-Remodeling Complexes Regulate the Hypoxia Response by Acting as Coactivators for a Subset of Hypoxia-Inducible Transcription Factor Target Genes

Sena¹,

Wang

2013

Molecular and Cellular Biology

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Chromatin remodeling is an active process, which represses or enables the access of transcription machinery to genes in response to external stimuli, including hypoxia. However, in hypoxia, the specific requirement, as well as the molecular mechanism by which the chromatin-remodeling complexes regulate gene expression, remains unclear. In this study, we report that the Brahma (BRM) and Brahma-related gene 1 (BRG1) ATPase-containing SWI/SNF chromatin-remodeling complexes promote the expression of the hypoxia-inducible transcription factor 1␣ (HIF1␣) and HIF2␣ genes and also promote hypoxic induction of a subset of HIF1 and HIF2 target genes. We show that BRG1 or BRM knockdown in Hep3B and RCC4T cells reduces hypoxic induction of HIF target genes, while reexpression of BRG1 or BRM in BRG1/BRM-deficient SW13 cells increases HIF target gene activation. Mechanistically, HIF1 and HIF2 increase the hypoxic induction of HIF target genes by recruiting BRG1 complexes to HIF target gene promoters, which promotes nucleosome remodeling of HIF target gene promoters in a BRG1 ATPase-dependent manner. Importantly, we found that the function of BRG1 complexes in hypoxic SW13 and RCC4T cells is dictated by the HIF-mediated hypoxia response and could be opposite from their function in normoxic SW13 and RCC4T cells.H ypoxia (Hx) is a common characteristic of many solid tumors. The Hx intratumoral microenvironment stabilizes hypoxia-inducible transcription factor 1␣ (HIF1␣) and HIF2␣, which are normally degraded under normoxia (Nx). The stabilized HIF1␣ and HIF2␣ proteins translocate to the nucleus, where they dimerize with the constitutive nuclear protein ARNT (the aryl hydrocarbon receptor nuclear translocator, also called HIF1␤) to form HIF1␣/ARNT (HIF1) and HIF2␣/ARNT (HIF2) heterodimers. HIF1 and HIF2 bind to HIF binding sites (HBS) on HIF target gene promoters and/or enhancers and transactivate genes involved in neovascularization, glycolysis, cellular proliferation, and metastasis. Thus, the HIF-mediated Hx transcriptional response is critical for tumor progression by allowing cancer cells to adapt to a low-oxygen environment (1-4). However, recent reports indicate that the HIF2-and particularly the HIF1-mediated Hx response can activate tumor-suppressive genes, such as Scgb3a, Bnip3, Bnip3L, Nix, MYC inhibitor Mxi, p21, and p27, in a cell-type-specific manner (5-10).It is well established that multiple transcription factors (TFs) are required to achieve maximal activation of target genes in response to a specific stimulus such as Hx. This multifactorial transcription complex has been termed the "enhanceosome." Individual TFs in the enhanceosome complex may promote transcription by recruiting RNA polymerase II/general TFs and/or by recruiting chromatin-modifying enzymes such as histone acetylase, CBP and p300, and the chromatin-remodeling SWI/SNF complex. In the context of the enhanceosome associated with the Hx response, two additional TFs, STAT3 and USF2, are required for maximal Hx response (11,12). STAT3 and USF2 function...

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STAT3 and HIF1α cooperatively activate HIF1 target genes in MDA-MB-231 and RCC4 cells

Cited by 194 publications

References 62 publications

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

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

TRPC1 is a differential regulator of hypoxia-mediated events and Akt signaling in PTEN-deficient breast cancer cells

BRG1 and BRM Chromatin-Remodeling Complexes Regulate the Hypoxia Response by Acting as Coactivators for a Subset of Hypoxia-Inducible Transcription Factor Target Genes

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