mTOR and HDAC Inhibitors Converge on the TXNIP/Thioredoxin Pathway to Cause Catastrophic Oxidative Stress and Regression of RAS-Driven Tumors

Malone, Clare F.; Emerson, Clifton W.; Ingraham, Rachel; Barbosa, William; Guerra, Stephanie; Yoon, Haejin; Liu, Lin L.; Michor, Franziska; Haigis, Marcia C.; Macleod, Kay F.; Maertens, Ophélia; Cichowski, Karen

doi:10.1158/2159-8290.cd-17-0177

Cited by 89 publications

(75 citation statements)

References 62 publications

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“…S2), as well as by previous studies [35][36][37]. BRG1-KD resulted in increased expression of LIF (STAT3 pathway activator [42]) and decreased SOCS1 (STAT3 pathway repressor [38,39]) in GICs, which was validated by qPCR ( Fig. 3A and Supporting Information, Fig.…”

Section: Brg1 Regulates An Stat3/txnip Pathwaysupporting

confidence: 82%

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Chromatin Remodeling Factor BRG1 Regulates Stemness and Chemosensitivity of Glioma Initiating Cells

et al. 2018

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Glioblastoma multiforme (GBM) is a highly aggressive and malignant brain tumor that is refractory to existing therapeutic regimens, which reflects the presence of stem-like cells, termed Glioma-Initiating Cells (GICs). The complex interactions between different signaling pathways and epigenetic regulation of key genes may be critical in the maintaining GICs in their stem-like state. Although several signaling pathways have been identified as being dysregulated in GBM, the prognosis of GBM patients remains miserable despite improvements in targeted therapies. In this report, we identified that BRG1, the catalytic subunit of the SWI/SNF chromatin remodeling complex, plays a fundamental role in maintaining GICs in their stem-like state. In addition, we identified a novel mechanism by which BRG1 regulates glycolysis genes critical for GICs. BRG1 downregulates the expression of TXNIP, a negative regulator of glycolysis. BRG1 knockdown also triggered the STAT3 pathway, which led to TXNIP activation. We further identified that TXNIP is an STAT3-regulated gene. Moreover, BRG1 suppressed the expression of interferon-stimulated genes, which are negatively regulated by STAT3 and regulate tumorigenesis. We further demonstrate that BRG1 plays a critical role in the drug resistance of GICs and in GIC-induced tumorigenesis. By genetic and pharmacological means, we found that inhibiting BRG1 can sensitize GICs to chemotherapeutic drugs, temozolomide and carmustine. Our studies suggest that BRG1 may be a novel therapeutic target in GBM. The identification of the critical role that BRG1 plays in GIC stemness and chemosensitivity will inform the development of better targeted therapies in GBM and possibly other cancers. Stem Cells 2018.

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Section: Brg1 Regulates An Stat3/txnip Pathwaysupporting

confidence: 82%

“…S1). TXNIP is involved in redox regulation and acts as a negative regulator of glycolysis [23,[40][41][42][43]. To assess whether BRG1 regulated a STAT3 pathway leading to TXNIP upregulation, lysates from control (scrambled shRNA), and BRG1-KD GBM6 and X16 GICs were prepared and immunoblotted.…”

Section: Brg1 Regulates An Stat3/txnip Pathwaymentioning

confidence: 99%

Chromatin Remodeling Factor BRG1 Regulates Stemness and Chemosensitivity of Glioma Initiating Cells

et al. 2018

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“…Since latent variables that are correlated with HDACs were found to be expressed most highly in cNFs (Cluster 5, Figure 6C, Figure S4C) and MPNSTs (cluster 1, Figure 6C, Figure 4A), compounds like CUDC-101 and analogs could be potential candidates for treating cNF and MPNST. Indeed, HDAC inhibitors were previously found to be efficacious in in vitro and in vivo models of MPNSTs [75,79]. Thus, our results further suggest that this therapeutic approach might be feasible in both MPNSTs and cNFs.…”

Section: Discussionsupporting

confidence: 68%

Integrative analysis identifies candidate tumor microenvironment and intracellular signaling pathways that define tumor heterogeneity in NF1

Banerjee

Allaway

Taroni

et al. 2020

Preprint

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Neurofibromatosis type 1 is a monogenic syndrome that gives rise to numerous symptoms including cognitive impairment, skeletal abnormalities, and growth of benign nerve sheath tumors. Nearly all NF1 patients develop cutaneous neurofibromas (cNFs), which occur on the skin surface, while 40-60% of patients develop plexiform neurofibromas (pNFs) which are deeply embedded in the peripheral nerves. Patients with pNFs have a ~10% lifetime chance of these tumors becoming malignant peripheral nerve sheath tumors (MPNSTs). These tumors have a severe prognosis and few treatment options other than surgery. Given the lack of therapeutic options available to patients with these tumors, identification of druggable pathways or other key molecular features could aid ongoing therapeutic discovery studies. In this work, we used statistical and machine learning methods to analyze 77 NF1 tumors with genomic data to characterize key signaling pathways that distinguish these tumors and identify candidates for drug development. We identified subsets of latent gene expression variables that may be important in the identification and etiology of cNFs, pNFs, other neurofibromas, and MPNSTs. Furthermore, we characterized the association between these latent variables and genetic variants, immune deconvolution predictions, and protein activity predictions.

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“…erefore, targeting antioxidant mechanisms might be a good therapeutic strategy for efficient radiotherapy [46]. Recent studies have reported that antioxidant mechanisms can be regulated by mTOR signaling [47][48][49]. In this review, the effects of mTOR inhibition on the antioxidative Keap1-NRF2 pathway in solid tumors during radiotherapy and the underlying mechanisms are assessed.…”

Section: Introductionmentioning

confidence: 99%

mTOR-Mediated Antioxidant Activation in Solid Tumor Radioresistance

Woo

Lee

Jung

et al. 2019

Journal of Oncology

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Radiotherapy is widely used for the treatment of cancer patients, but tumor radioresistance presents serious therapy challenges. Tumor radioresistance is closely related to high levels of mTOR signaling in tumor tissues. Therefore, targeting the mTOR pathway might be a strategy to promote solid tumor sensitivity to ionizing radiation. Radioresistance is associated with enhanced antioxidant mechanisms in cancer cells. Therefore, examination of the relationship between mTOR signaling and antioxidant mechanism-linked radioresistance is required for effective radiotherapy. In particular, the effect of mTOR signaling on antioxidant glutathione induction by the Keap1-NRF2-xCT pathway is described in this review. This review is expected to assist in the identification of therapeutic adjuvants to increase the efficacy of radiotherapy.

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mTOR and HDAC Inhibitors Converge on the TXNIP/Thioredoxin Pathway to Cause Catastrophic Oxidative Stress and Regression of RAS-Driven Tumors

Cited by 89 publications

References 62 publications

Chromatin Remodeling Factor BRG1 Regulates Stemness and Chemosensitivity of Glioma Initiating Cells

Chromatin Remodeling Factor BRG1 Regulates Stemness and Chemosensitivity of Glioma Initiating Cells

Integrative analysis identifies candidate tumor microenvironment and intracellular signaling pathways that define tumor heterogeneity in NF1

mTOR-Mediated Antioxidant Activation in Solid Tumor Radioresistance

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