IRE1α RNase–dependent lipid homeostasis promotes survival in Myc-transformed cancers

Xie, Hong; Tang, Chih-Hang Anthony; Song, Jun; Mancuso, Anthony A.; Valle, Juan R. Del; Cao, Jin; Xiang, Yan; Dang, Chi V.; Lan, Roy; Sanchez, Danielle J.; Keith, Brian; Hu, Chih‐Chi Andrew; Simon, M. Celeste

doi:10.1172/jci95864

Cited by 100 publications

(75 citation statements)

References 62 publications

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“…Analysis by transmission electron microscopy revealed a highly dilated ER in TNBC cell lines grown in vitro, suggesting volumetric ER expansion and adaptation to stress (26). Similar changes were observed in MYC expressing B-cell lymphomas (30).…”

Section: Introductionsupporting

confidence: 54%

“…TNBC also coopts the UPR, as shown by seminal published work implicating XBP1s in conjunction with HIF1 in driving TNBC tumor angiogenesis and progression under hypoxia (26). More recent studies also have linked the IRE1-XBP1s axis to the oncogenic transcription factor MYC-a potent driver of proliferation and protein synthesis (27)-in TNBC (28), prostate cancer (29), and B-cell lymphoma (30). Pharmacologic inhibition of IRE1 via its RNase domain markedly augmented the effectiveness of taxane chemotherapy in cellline-based or patient-derived xenograft TNBC models (28,31).…”

Section: Introductionmentioning

confidence: 97%

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IRE1α Disruption in Triple-Negative Breast Cancer Cooperates with Antiangiogenic Therapy by Reversing ER Stress Adaptation and Remodeling the Tumor Microenvironment

Harnoss¹,

Thomas²,

Reichelt³

et al. 2020

Cancer Research

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Cancer cells exploit the unfolded protein response (UPR) to mitigate endoplasmic reticulum (ER) stress caused by cellular oncogene activation and a hostile tumor microenvironment (TME). The key UPR sensor IRE1α resides in the ER and deploys a cytoplasmic kinase-endoribonuclease module to activate the transcription factor XBP1s, which facilitates ER-mediated protein folding. Studies of triple-negative breast cancer (TNBC)-a highly aggressive malignancy with a dismal post-treatment prognosisimplicate XBP1s in promoting tumor vascularization and progression. However, it remains unknown whether IRE1α adapts the ER in TNBC cells and modulates their TME, and whether IRE1α inhibition can enhance anti-angiogenic therapy-previously found to be ineffective in TNBC patients. To gauge IRE1α function, we defined an XBP1s-dependent gene signature, which revealed significant IRE1α pathway activation in multiple solid cancers, including TNBC. IRE1α knockout in TNBC cells markedly reversed substantial ultrastructural expansion of the ER within these cells upon growth in vivo. IRE1α disruption also led to significant remodeling of the cellular TME, increasing pericyte numbers while decreasing cancer-associated fibroblasts and myeloid-derived suppressor cells. Pharmacological IRE1α kinase inhibition strongly attenuated growth of cell-line-based and patient-derived TNBC xenografts in mice and synergized with anti-VEGF-A treatment to cause tumor stasis or regression. Thus, TNBC cells critically rely on IRE1α to adapt their ER to in vivo stress and to adjust the TME to facilitate malignant growth. TNBC reliance on IRE1α is an important vulnerability that can be uniquely exploited in combination with anti-angiogenic therapy as a promising new biologic approach to combat this lethal disease. Statement of significance Pharmacologic IRE1α kinase inhibition reverses ultrastructural distension of the ER, normalizes the tumor vasculature, and remodels the cellular tumor microenvironment, attenuating TNBC growth in mice. Research.

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Section: Introductionsupporting

confidence: 54%

Section: Introductionmentioning

confidence: 97%

IRE1α Disruption in Triple-Negative Breast Cancer Cooperates with Antiangiogenic Therapy by Reversing ER Stress Adaptation and Remodeling the Tumor Microenvironment

Harnoss¹,

Thomas²,

Reichelt³

et al. 2020

Cancer Research

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“…Reaction was quenched with 125 mM glycine. ChIP was performed as previously described (55) with XBP1 antibody (catalog 619502, BioLegend), MYC antibody (catalog sc-764, Santa Cruz Biotechnology Inc.), P300 antibody (catalog sc-585, Santa Cruz Biotechnology Inc.), SRC3 antibody (catalog 2126, Cell Signaling Technology), CBP ment of IRE1/XBP1 signaling for MYC deregulation in Burkitt's lymphoma and neuroblastoma (50). These 2 studies suggest there may be a potentially significant clinical impact of targeting IRE1/XBP1, as we provide a mechanism-based pharmacological approach for the treatment of MYC-driven human tumors.…”

Section: Discussionmentioning

confidence: 99%

“…Determination of EC 50 . WT or IRE1-KO SUM159 cells were seeded into 6-well plates at 500 cells per well and treated with DMSO or various doses of 8866 for 10 days.…”

Section: Methodsmentioning

confidence: 99%

Pharmacological targeting of MYC-regulated IRE1/XBP1 pathway suppresses MYC-driven breast cancer

Zhao¹,

Cao

et al. 2018

Journal of Clinical Investigation

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169

160

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The unfolded protein response (UPR) is a cellular homeostatic mechanism that is activated in many human cancers and plays pivotal roles in tumor progression and therapy resistance. However, the molecular mechanisms for UPR activation and regulation in cancer cells remain elusive. Here, we show that oncogenic MYC regulates the inositol-requiring enzyme 1 (IRE1)/X-box binding protein 1 (XBP1) branch of the UPR in breast cancer via multiple mechanisms. We found that MYC directly controls IRE1 transcription by binding to its promoter and enhancer. Furthermore, MYC forms a transcriptional complex with XBP1, a target of IRE1, and enhances its transcriptional activity. Importantly, we demonstrate that XBP1 is a synthetic lethal partner of MYC. Silencing of XBP1 selectively blocked the growth of MYC-hyperactivated cells. Pharmacological inhibition of IRE1 RNase activity with small molecule inhibitor 8866 selectively restrained the MYC-overexpressing tumor growth in vivo in a cohort of preclinical patient-derived xenograft models and genetically engineered mouse models. Strikingly, 8866 substantially enhanced the efficacy of docetaxel chemotherapy, resulting in rapid regression of MYC-overexpressing tumors. Collectively, these data establish the synthetic lethal interaction of the IRE1/XBP1 pathway with MYC hyperactivation and provide a potential therapy for MYC-driven human breast cancers.

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“…It is well known that IRE1 mediates UPR mainly by regulating XBP1 mRNA splicing in response to ERS 73 . IRE1α/XBP1 pathway is a potential therapeutic target for Myc-driven cancers and multiple myeloma 74,75 . However, IRE1 also exhibits XBP1-independent biochemical activities just shown in current study and previous reports 76,77 .…”

Section: Discussionmentioning

confidence: 99%

Calreticulin Promotes EMT in Pancreatic Cancer via Mediating Ca2+ Dependent Acute and Chronic Endoplasmic Reticulum Stress

Sheng

Wang

Tang

et al. 2020

Preprint

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Background: Our previous study showed that calreticulin (CRT) promoted EGF-induced epithelial-mesenchymal transition (EMT) in pancreatic cancer (PC) via Integrin/EGFR-ERK/MAPK signaling. We next investigated the novel signaling pathway and molecular mechanism involving the oncogenic role of CRT in PC development. Methods: We investigated the potential role and mechanism of CRT in regulating Ca2+ dependent acute and chronic endoplasmic reticulum stress (ERS)-induced EMT in PC in vitro and vivo.Results: Thapsigargin (TG) induced acute ERS via increasing intracellular free Ca2+ in PC cells, which was reversed by CRT silencing. Additionally, CRT silencing inhibited TG-induced EMT in vitro by reversing TG-induced changes of the key proteins in EMT signaling (ZO-1, E-cadherin and Slug) and ERK/MAPK signaling (pERK), and inhibiting TG-promoted cell invasion and migration. Meanwhile, CRT was coimmunoprecipitated with inositol-requiring enzyme 1α (IRE1α, one of the key stressors in unfolded protein response) in vitro and its silencing led to the chronic ERS via upregulating IRE1α but independent of X-box-binding protein 1 (XBP1). Moreover, CRT silencing inhibited IRE1α silencing-promoted EMT, including inhibiting the activation of EMT and ERK/MAPK signaling and the promotion of cell mobility. In addition, CRT silencing decreased subcutaneous tumor size and distant liver metastasis in vivo. Furthermore, a negative relationship between CRT and IRE1α was observed in vivo and in clinical PC samples, which coordinately promoted the advanced clinical stages and poor prognosis of PC patients. Conclusions: CRT promoted EMT in PC via mediating Ca2+ dependent TG-induced acute ERS and IRE1α-mediated chronic ERS via Slug and ERK/MAPK signaling.

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IRE1α RNase–dependent lipid homeostasis promotes survival in Myc-transformed cancers

Cited by 100 publications

References 62 publications

IRE1α Disruption in Triple-Negative Breast Cancer Cooperates with Antiangiogenic Therapy by Reversing ER Stress Adaptation and Remodeling the Tumor Microenvironment

IRE1α Disruption in Triple-Negative Breast Cancer Cooperates with Antiangiogenic Therapy by Reversing ER Stress Adaptation and Remodeling the Tumor Microenvironment

Pharmacological targeting of MYC-regulated IRE1/XBP1 pathway suppresses MYC-driven breast cancer

Calreticulin Promotes EMT in Pancreatic Cancer via Mediating Ca2+ Dependent Acute and Chronic Endoplasmic Reticulum Stress

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