mTORC1 inhibition attenuates necroptosis through RIP1 inhibition-mediated TFEB activation

Abe, Koki; Yano, Toshiyuki; Tanno, Masaya; Miki, Takayuki; Kuno, Atsushi; Sato, Tatsuya; Kouzu, Hidemichi; Nakata, Kei; Ohwada, Wataru; Kimura, Yoshinobu; Sugawara, Hirohito; Shibata, Satoru; Igaki, Yusuke; Ino, Shoya; Miura, Tetsuji

doi:10.1016/j.bbadis.2019.165552

Cited by 44 publications

(31 citation statements)

References 55 publications

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“…Rapamycin is an inhibitor that interferes with the inhibition of the mTOR signaling pathway, so it is a TFEB agonist [94]. In TNF/ zVAD-treated cells, rapamycin increases nuclear localization of TFEB and promotes autolysosome formation in a TFEB-dependent manner [88]. Rapamycin also suppresses TNF/zVAD-induced RIP1-S166 phosphorylation and increases phosphorylation of RIP1-S320, which is an inhibitory phosphorylation site [88].…”

Section: Rapamycinmentioning

confidence: 99%

“…In TNF/ zVAD-treated cells, rapamycin increases nuclear localization of TFEB and promotes autolysosome formation in a TFEB-dependent manner [88]. Rapamycin also suppresses TNF/zVAD-induced RIP1-S166 phosphorylation and increases phosphorylation of RIP1-S320, which is an inhibitory phosphorylation site [88]. Since TFEB is phosphorylated before activation, when the inhibit phosphorylation sites are suppressed, TFEB is more likely to be activated.…”

Section: Rapamycinmentioning

confidence: 99%

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TFEB Biology and Agonists at a Glance

Chen

Dai

Liu

et al. 2021

Cells

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Autophagy is a critical regulator of cellular survival, differentiation, development, and homeostasis, dysregulation of which is associated with diverse diseases including cancer and neurodegenerative diseases. Transcription factor EB (TFEB), a master transcriptional regulator of autophagy and lysosome, can enhance autophagic and lysosomal biogenesis and function. TFEB has attracted a lot of attention owing to its ability to induce the intracellular clearance of pathogenic factors in a variety of disease models, suggesting that novel therapeutic strategies could be based on the modulation of TFEB activity. Therefore, TFEB agonists are a promising strategy to ameliorate diseases implicated with autophagy dysfunction. Recently, several TFEB agonists have been identified and preclinical or clinical trials are applied. In this review, we present an overview of the latest research on TFEB biology and TFEB agonists.

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Section: Rapamycinmentioning

confidence: 99%

Section: Rapamycinmentioning

confidence: 99%

TFEB Biology and Agonists at a Glance

Chen

Dai

Liu

et al. 2021

Cells

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“…Taken together, this suggested that the LEC-specific inactivation of mTOR results in the activation of hepatocellular necroptosis in the context of liver regeneration due to partial hepatectomy. However, this is not supported by the published literature, where several independent groups have reported a functional importance of mTOR activation for the execution of necroptosis(63)(64)(65). We cannot rule out the possibility that the focal necrotic areas in the mTOR LEC mice originated from mTOR-proficient hepatocytes.…”

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confidence: 57%

Enhanced inflammatory response mediated by parenchymal cells associates with resistance towards mTOR inhibition

Jiao¹,

Eickhoff²,

Jumpertz³

et al. 2020

Preprint

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Activation of the mTOR pathway is frequently found in cancer, but mTOR inhibitors have thus far failed to demonstrate significant antiproliferative efficacy in the majority of cancer types. Besides cancer cell-intrinsic resistance mechanisms, it is conceivable that mTOR inhibitors impact on non-malignant host cells in a manner that ultimately supports resistance of cancer cells. Against this background, we sought to analyze the functional consequences of mTOR inhibition in hepatocytes for the growth of metastatic colon cancer. To this end, we established a liver epithelial cell (LEC)-specific knock-out (KO) of mTOR (mTORLEC mice). We used these mice to characterize the growth of colorectal liver metastases with and without partial hepatectomy to model different clinical settings. While the LEC-specific loss of mTOR remained without effect on metastasis growth in intact liver, partial liver resection resulted in the formation of larger metastases in mTORLEC mice compared to wildtype controls. This was accompanied by significantly enhanced inflammatory activity in LEC-specific mTOR KO livers after partial liver resection. Analysis of NF-κB target gene expression and immunohistochemistry of p65 displayed a significant activation of NF-κB in mTORLEC mice, suggesting a functional importance of this pathway for the observed inflammatory phenotype. Taken together, we show an unexpected acceleration of liver metastases upon deletion of mTOR in liver epithelial cells. Our results support the notion that non-malignant host cells can contribute to resistance against mTOR inhibitors and encourage to test if anti-inflammatory drugs are able to improve the efficacy of mTOR inhibitor for cancer therapy.

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“…This proposition now has support from two recent studies that collected evidence from cultured H9c2 cells suggesting a major contribution from impaired autophagy to the induction of necroptosis by TNFα. 48, 49 According to these reports, RIPK1-RIPK3 interaction and necroptosis induced by the combined treatment with TNFα and z-VAD-fmk (a broad spectrum caspase inhibitor) were associated with suppression of autophagic flux, 48 improving autophagic flux via mTORC1 inhibition suppressed the necroptosis in an autophagy- and transcription factor EB (TFEB; a master regulator of the ALP)-dependent manner, 48, 49 and MPT does not to play a major role in the execution of necroptosis. 48 This scenario starkly resembles what we have unveiled in the Cops8 CKO mouse myocardium.…”

Section: Discussionmentioning

confidence: 99%

The COP9 Signalosome Suppresses Cardiomyocyte Necroptosis

Peng

Wang

Lewno

et al. 2019

Preprint

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BackgroundLoss of cardiomyocyte (CMs) due to apoptosis and regulated necrosis contributes to heart failure. However, the molecular mechanisms governing regulated CM necrosis remain obscure. The COP9 signalosome (CSN) formed by 8 unique protein subunits (COPS1 through COPS8) functions to deneddylate Cullin-RING ligases (CRLs), thereby regulating the functioning of the CRLs. Mice with CM-restricted knockout of Cops8 (Cops8-cko) die prematurely, following reduced myocardial performance of autophagy and the ubiquitin-proteasome system (UPS) as well as massive CM necrosis. This study was aimed to determine the nature and underlying mechanisms of the CM necrosis in Cops8-cko mice.MethodsWe examined myocardial expression and activities of key proteins that reflect the status of the RIPK1-RIPK3 pathway, redox, and caspase 8 in Cops8-cko mice. Moreover, we used in vivo CM uptake of Evan’s blue dye (EBD) as an indicator of necrosis and performed Kaplan-Meier survival analyses to test whether treatment with a RIPK1 kinase inhibitor (necrostatin-1) or an antioxidant (N-acetyl-L-cysteine), global knockout of the RIPK3 or the Ppif gene, CM-restricted knockout of the Nrf2 gene, or cardiac HMOX1 overexpression could rescue the Cops8-cko phenotype.ResultsCompared with littermate control mice, myocardial protein levels of RIPK1, RIPK3, MLKL, the RIPK1-bound RIPK3, protein carbonyls, full-length caspase 8, Nrf2, Ser40-phosphorylated Nrf2 and BCL2, as well as histochemical staining of superoxide anions were significantly increased but the cleaved caspase 8 and the overall caspase 8 activity were markedly decreased in Cops8-cko mice, indicating that the RIPK1-RIPK3 and the Nrf2 pathways are activated and caspase 8 activation is suppressed by Cops8-cko. Continuous necrostatin-1 infusion initiated at 2 weeks of age nearly completely blocked CM necrosis at 3 weeks and markedly delayed premature death of Cops8-cko mice. RIPK3 haploinsufficiency or cardiac-specific Nrf2 heterozygous knockout discernably attenuated CM necrosis and/or delayed mouse premature death; conversely, Ppif knockout, N-acetyl-L-cysteine treatment, and cardiac overexpression of HMOX1 exacerbated CM necrosis and mouse premature death.ConclusionsCardiac Cops8/CSN malfunction causes RIPK1-RIPK3 mediated CM necroptosis in mice; sustained Nrf2 activation and reductive stress pivot cardiomyocytes to necroptosis when autophagy and the UPS are impaired; and the CSN plays an indispensable role in suppressing CM necroptosis.

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mTORC1 inhibition attenuates necroptosis through RIP1 inhibition-mediated TFEB activation

Cited by 44 publications

References 55 publications

TFEB Biology and Agonists at a Glance

TFEB Biology and Agonists at a Glance

Enhanced inflammatory response mediated by parenchymal cells associates with resistance towards mTOR inhibition

The COP9 Signalosome Suppresses Cardiomyocyte Necroptosis

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