Interleukin-6 influences stress-signalling by reducing the expression of the mTOR-inhibitor REDD1 in a STAT3-dependent manner

Jessica, Pinno; Bongartz, Hannes; Klepsch, Oliver; Wundrack, Nicole; Poli, Valeria; Schaper, Fred; Dittrich, Anna

doi:10.1016/j.cellsig.2016.04.004

Cited by 39 publications

(36 citation statements)

References 62 publications

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“…Abnormalities of Ddit4-mediated signaling promote tumorigenesis (Ellisen, 2005;Pineau et al, 2010). Moreover, Ddit4 expression depends on the activation of STAT3 (Pinno et al, 2016). In the present study, Ddit4 was decreased and reversed after rapamycin given, indicating mTORC1 negative feedback on Ddit4.…”

Section: Discussionsupporting

confidence: 57%

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Defects in mTORC1 Network and mTORC1-STAT3 Pathway Crosstalk Contributes to Non-inflammatory Hepatocellular Carcinoma

Zhang

Wang

et al. 2020

Front. Cell Dev. Biol.

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Background and Aims: Mammalian target of rapamycin complex 1 (mTORC1) is frequently hyperactivated in hepatocellular carcinoma (HCC). Cases of HCC without inflammation and cirrhosis are not rarely seen in clinics. However, the molecular basis of non-inflammatory HCC remains unclear. Methods: Spontaneous non-inflammatory HCC in mice was triggered by constitutive elevation of mTORC1 by liver-specific TSC1 knockout (LTsc1KO). A multi-omics approach was utilized on tumor tissues to better understand the molecular basis for the development of HCC in the LTsc1KO model. Results: We showed that LTsc1KO in mice triggered spontaneous non-inflammatory HCC, with molecular characteristics similar to those of diethylnitrosamine-mediated non-cirrhotic HCC. Mitochondrial and autophagy defects, as well as hepatic metabolic disorder were manifested in HCC development by LTsc1KO. mTORC1 activation on its own regulated an oncogenic network (DNA-damage-inducible transcript 4, nuclear protein 1, and fibroblast growth factor 21), and mTORC1-signal transducer and activator of transcription pathway crosstalk that altered specific metabolic pathways contributed to the development of non-inflammatory HCC. Conclusion: Our findings reveal the mechanisms of mTORC1-driven non-inflammatory HCC and provide insight into further development of a protective strategy against noninflammatory HCC.

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Section: Discussionsupporting

confidence: 57%

“…Ddit4 is a constant modulator of p-Akt in response to growth factors and nutrients (Dennis et al, 2014), and its expression depends on activation of STAT3 (Pinno et al, 2016). In the present study, LTsc1KO mice demonstrated reduced expression of p-Akt, p-STAT3 and Ddit4 (Figure 5B).…”

Section: Crosstalk Between Mtorc1 and The Stat3 Pathway Was Linked Tosupporting

confidence: 61%

Defects in mTORC1 Network and mTORC1-STAT3 Pathway Crosstalk Contributes to Non-inflammatory Hepatocellular Carcinoma

Zhang

Wang

et al. 2020

Front. Cell Dev. Biol.

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“…These results indicate that REDD1mediated autophagy may be a novel target to sensitize BUC cells to Taxol chemotherapy. REDD1 expression can be induced by MAPK and PKA signaling pathways (42,43), and can also be negatively regulated by other factors such as Ezrin, T-cell acute leukemia 1 (TAL1), and IL6 (44)(45)(46). Here we make the novel discovery that REDD1 is negatively regulated by miR-22.…”

Section: Discussionmentioning

confidence: 98%

Inhibition of REDD1 Sensitizes Bladder Urothelial Carcinoma to Paclitaxel by Inhibiting Autophagy

Zeng

Liu

Cao

et al. 2018

Clinical Cancer Research

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Regulated in development and DNA damage response-1 (REDD1) is a stress-related protein and is involved in the progression of cancer. The role and regulatory mechanism of REDD1 in bladder urothelial carcinoma (BUC), however, is yet unidentified. The expression of REDD1 in BUC was detected by Western blot analysis and immunohistochemistry (IHC). The correlation between REDD1 expression and clinical features in patients with BUC were assessed. The effects of REDD1 on cellular proliferation, apoptosis, autophagy, and paclitaxel sensitivity were determined both and Then the targeted-regulating mechanism of REDD1 by miRNAs was explored. Here the significant increase of REDD1 expression is detected in BUC tissue, and REDD1 is first reported as an independent prognostic factor in patients with BUC. Silencing REDD1 expression in T24 and EJ cells decreased cell proliferation, increased apoptosis, and decreased autophagy, whereas the ectopic expression of REDD1 in RT4 and BIU87 cells had the opposite effect. In addition, the REDD1-mediated proliferation, apoptosis, and autophagy are found to be negatively regulated by miR-22 , which intensify the paclitaxel sensitivity via inhibition of the well-acknowledged REDD1-EEF2K-autophagy axis. AKT/mTOR signaling initially activated or inhibited in response to silencing or enhancing REDD1 expression and then recovered rapidly. Finally, the inhibited REDD1 expression by either RNAi or miR-22 sensitizes BUC tumor cells to paclitaxel in a subcutaneous transplant carcinoma model REDD1 is confirmed as an oncogene in BUC, and antagonizing REDD1 could be a potential therapeutic strategy to sensitize BUC cells to paclitaxel. .

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“…23 Interestingly, IL-6 can activate mTOR in a STAT3 dependent or independent manner. 24 Whether our proposed drugs can be indeed repurposed for COVID-19 therapies now needs to be carefully tested in in vitro SARS-CoV-2 infection models and in in vivo COVID-19 disease models.…”

Section: Discussionmentioning

confidence: 99%

Dysregulation in mTOR/HIF-1 signaling identified by proteo-transcriptomics of SARS-CoV-2 infected cells

Appelberg

Gupta

Ambikan

et al. 2020

Preprint

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26How Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infections engage 27 cellular host pathways and innate immunity in infected cells remain largely elusive. We 28 performed an integrative proteo-transcriptomics analysis in SARS-CoV-2 infected HuH7 cells to 29 map the cellular response to the invading virus over time. We identified four pathways, ErbB, 30 HIF-1, mTOR and TNF signaling, among others that were markedly modulated during the course 31 of the SARS-CoV-2 infection in vitro. Western blot validation of the downstream effector 32 molecules of these pathways revealed a significant reduction in activated S6K1 and 4E-BP1 at 72 33 hours post infection. Unlike other human respiratory viruses, we found a significant inhibition of 34 HIF-1α through the entire time course of the infection, suggesting a crosstalk between the SARS-35

show abstract

Interleukin-6 influences stress-signalling by reducing the expression of the mTOR-inhibitor REDD1 in a STAT3-dependent manner

Cited by 39 publications

References 62 publications

Defects in mTORC1 Network and mTORC1-STAT3 Pathway Crosstalk Contributes to Non-inflammatory Hepatocellular Carcinoma

Defects in mTORC1 Network and mTORC1-STAT3 Pathway Crosstalk Contributes to Non-inflammatory Hepatocellular Carcinoma

Inhibition of REDD1 Sensitizes Bladder Urothelial Carcinoma to Paclitaxel by Inhibiting Autophagy

Dysregulation in mTOR/HIF-1 signaling identified by proteo-transcriptomics of SARS-CoV-2 infected cells

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