Impact of Pyrrolidine Dithiocarbamate and Interleukin-6 on Mammalian Target of Rapamycin Complex 1 Regulation and Global Protein Translation

Song, Shaoming; Abdelmohsen, Kotb; Zhang, Yongqing; Becker, Kevin G.; Gorospe, Myriam; Bernier, Michel

doi:10.1124/jpet.111.185678

Cited by 10 publications

(11 citation statements)

References 39 publications

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“…This finding is underlined by the observation that reduction of STAT3 phosphorylation by pyrrolidine dithiocarbamate (PDTC) correlates with reduction of mTOR signalling [38]. Of note, PDTC does not specifically inhibit STAT3 activation as it also inhibits e.g.…”

Section: Discussionmentioning

confidence: 72%

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

Jessica

Bongartz

Klepsch

et al. 2016

Cellular Signalling

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Abstract:Interleukin 6 is a pleiotropic cytokine and a strong activator of Mammalian Target of Rapamycin (mTOR). In contrast, mTOR activity is negatively regulated by Regulated in Development and DNA Damage Responses 1 (REDD1). Expression of REDD1 is induced by cellular stressors such as glucocorticoids and DNA damaging agents. We show that the expression of basal as well as stress-induced REDD1 is reduced by IL-6. The reduction of REDD1 expression by IL-6 is independent of proteasomal or caspase-mediated degradation of REDD1 protein. Instead, induction of REDD1 mRNA is reduced by IL-6. The regulation of REDD1 expression by interleukin 6 (IL-6) is independent of Phosphatidylinositide-3-Kinase (PI3K) and Mitogen-Activated Protein Kinase (MAPK) signalling but depends on the expression and activation of Signal Transducer and Activator of Transcription 3 (STAT3). Furthermore, the reduction of basal REDD1 expression by IL-6 correlates with IL-6-induced activation of mTOR signalling. Inhibition of STAT3 activation blocks IL-6-induced mTOR activation. In summary, we present a novel STAT3-dependent mechanism of both IL-6-induced activation of mTOR and IL-6-dependent reversion of stress-induced inhibition of mTOR activity.

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Section: Discussionmentioning

confidence: 72%

“…As mentioned above Song et al show that PDTC reduces IL-6-induced mTOR signalling by induction of REDD1 [38]. PDTC-induced REDD1 expression is not reduced by IL-6.…”

Section: Discussionmentioning

confidence: 92%

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

Jessica

Bongartz

Klepsch

et al. 2016

Cellular Signalling

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“…These findings are in contrast to systemic IL-6 inhibition, as an IL-6 receptor antibody was unable to rescue the suppression of muscle protein synthesis during the progression of cancer cachexia [ 27 ]. However, PDTC treatment has been shown to increase global protein translational capacity in non-muscle cells through a rapamycin independent mechanism [ 15 ]. Whether this mechanism occurs in skeletal muscle requires further investigation.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, PDTC has been shown to suppress inflammatory processes through the inhibition of nuclear factor κB (NF-κB) signaling [ 12 – 14 ]. Moreover, gene expression related to protein translation and oxidative capacity can be upregulated by PDTC treatment in hepatocarcinoma (HepG2) cells [ 15 , 16 ]. Given that the previously mentioned signaling pathways are disrupted in several wasting conditions, there is growing interest to determine the therapeutic potential of PDTC treatment.…”

Section: Introductionmentioning

confidence: 99%

Short-term pyrrolidine dithiocarbamate administration attenuates cachexia-induced alterations to muscle and liver in ApcMin/+ mice

et al. 2016

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Cancer cachexia is a complex wasting condition characterized by chronic inflammation, disrupted energy metabolism, and severe muscle wasting. While evidence in pre-clinical cancer cachexia models have determined that different systemic inflammatory inhibitors can attenuate several characteristics of cachexia, there is a limited understanding of their effects after cachexia has developed, and whether short-term administration is sufficient to reverse cachexia-induced signaling in distinctive target tissues. Pyrrolidine dithiocarbamate (PDTC) is a thiol compound having anti-inflammatory and antioxidant properties which can inhibit STAT3 and nuclear factor κB (NF-κB) signaling in mice. This study examined the effect of short-term PDTC administration to ApcMin/+ mice on cachexia-induced disruption of skeletal muscle protein turnover and liver metabolic function. At 16 weeks of age ApcMin/+ mice initiating cachexia (7% BW loss) were administered PDTC (10mg/kg bw/d) for 2 weeks. Control ApcMin/+ mice continued to lose body weight during the treatment period, while mice receiving PDTC had no further body weight decrease. PDTC had no effect on either intestinal tumor burden or circulating IL-6. In muscle, PDTC rescued signaling disrupting protein turnover regulation. PDTC suppressed the cachexia induction of STAT3, increased mTORC1 signaling and protein synthesis, and suppressed the induction of Atrogin-1 protein expression. Related to cachectic liver metabolic function, PDTC treatment attenuated glycogen and lipid content depletion independent to the activation of STAT3 and mTORC1 signaling. Overall, these results demonstrate short-term PDTC treatment to cachectic mice attenuated cancer-induced disruptions to muscle and liver signaling, and these changes were independent to altered tumor burden and circulating IL-6.

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“…Notably, activated STAT3 promotes the expression of microRNA-21 [ 255 - 257 ]. Furthermore, IL-6-mediated activation of mTORC1 [ 258 ] may further increase ER-stress-mediated β-cell apoptosis.…”

Section: Discussionmentioning

confidence: 99%

The Pathogenic Role of Persistent Milk Signaling in mTORC1- and Milk- MicroRNA-Driven Type 2 Diabetes Mellitus

Melnik

2015

CDR

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Milk, the secretory product of the lactation genome, promotes growth of the newborn mammal. Milk delivers insulinotropic amino acids, thus maintains a molecular crosstalk with the pancreatic β-cell of the milk recipient. Homeostasis of β-cells and insulin production depend on the appropriate magnitude of mTORC1 signaling. mTORC1 is activated by branched-chain amino acids (BCAAs), glutamine, and palmitic acid, abundant nutrient signals of cow´s milk. Furthermore, milk delivers bioactive exosomal microRNAs. After milk consumption, bovine microRNA-29b, a member of the diabetogenic microRNA-29-family, reaches the systemic circulation and the cells of the milk consumer. MicroRNA-29b downregulates branched-chain α-ketoacid dehydrogenase, a potential explanation for increased BCAA serum levels, the metabolic signature of insulin resistance and type 2 diabetes mellitus (T2DM). In non-obese diabetic mice, microRNA-29b downregulates the anti-apoptotic protein Mcl-1, which leads to early β-cell death. In all mammals except Neolithic humans, milk-driven mTORC1 signaling is physiologically restricted to the postnatal period. In contrast, chronic hyperactivated mTORC1 sig-naling has been associated with the development of age-related diseases of civilization including T2DM. Notably, chronic hyperactivation of mTORC1 enhances endoplasmic reticulum stress that promotes apoptosis. In fact, hyperactivated β-cell mTORC1 signaling induced early β-cell apoptosis in a mouse model. The EPIC-InterAct Study demonstrated an association between milk consumption and T2DM in France, Italy, United Kingdom, Germany, and Sweden. In contrast, fermented milk products and cheese exhibit an inverse correlation. Since the early 1950´s, refrigeration technology allowed widespread consumption of fresh pasteurized milk, which facilitates daily intake of bioactive bovine microRNAs. Persistent uptake of cow´s milk-derived microRNAs apparently transfers an overlooked epigenetic diabetogenic program that should not reach the human food chain.

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Impact of Pyrrolidine Dithiocarbamate and Interleukin-6 on Mammalian Target of Rapamycin Complex 1 Regulation and Global Protein Translation

Cited by 10 publications

References 39 publications

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

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

Short-term pyrrolidine dithiocarbamate administration attenuates cachexia-induced alterations to muscle and liver in ApcMin/+ mice

The Pathogenic Role of Persistent Milk Signaling in mTORC1- and Milk- MicroRNA-Driven Type 2 Diabetes Mellitus

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