mTOR Pathways in Cancer and Autophagy

Paquette, Mathieu; El–Houjeiri, Leeanna; Pause, Arnim

doi:10.3390/cancers10010018

Cited by 251 publications

(235 citation statements)

References 156 publications

(189 reference statements)

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“…Our studies revealed inhibition of mTOR and its activity in both mouse models of ALD and in humans. Inhibition of mTOR activity was shown to increase autophagy . We found disruption of autophagy at the lysosomal level.…”

Section: Discussionmentioning

confidence: 61%

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Dysregulated Autophagy and Lysosome Function Are Linked to Exosome Production by Micro‐RNA 155 in Alcoholic Liver Disease

et al. 2019

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Cellular homeostais, that is normally maintained through autophagy, is disrupted in alcoholic liver disease (ALD). Because autophagy and exosome biogenesis share common elements, we hypothesized that increased exosome production in ALD may be linked to disruption of autophagic function. We found impaired autophagy both in ALD and alcoholic hepatitis (AH) mouse models and human livers with ALD as indicated by increased hepatic p62 and LC3‐II levels. Alcohol reduced autophagy flux in vivo in chloroquine‐treated mice as well as in vitro in hepatocytes and macrophages treated with bafilomycin A. Our results revealed that alcohol targets multiple steps in the autophagy pathway. Alcohol‐related decrease in mechanistic target of rapamycin (mTOR) and Ras homolog enriched in brain (Rheb), that initiate autophagy, correlated with increased Beclin1 and autophagy‐related protein 7 (Atg7), proteins involved in phagophore‐autophagosome formation, in ALD. We found that alcohol disrupted autophagy function at the lysosomal level through decreased lysosomal‐associated membrane protein 1 (LAMP1) and lysosomal‐associated membrane protein 2 (LAMP2) in livers with ALD. We identified that micro‐RNA 155 (miR‐155), that is increased by alcohol, targets mTOR, Rheb, LAMP1, and LAMP2 in the authophagy pathway. Consistent with this, miR‐155‐deficient mice were protected from alcohol‐induced disruption of autophagy and showed attenuated exosome production. Mechanistically, down‐regulation of LAMP1 or LAMP2 increased exosome release in hepatocytes and macrophages in the presence and absence of alcohol. These results suggested that the alcohol‐induced increase in exosome production was linked to disruption of autophagy and impaired autophagosome and lysosome function. Conclusion: Alcohol affects multiple genes in the autophagy pathway and impairs autophagic flux at the lysosome level in ALD. Inhibition of LAMP1 and LAMP2 promotes exosome release in ALD. We identified miR‐155 as a mediator of alcohol‐related regulation of autophagy and exosome production in hepatocytes and macrophages.

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Section: Discussionmentioning

confidence: 61%

“…We found disruption of autophagy at the lysosomal level. Apart from its role in autophagy, mTOR is a central regulator of cell growth, proliferation, and survival in response to nutritional status, growth factor, and stress signals . A recent study showed a role of mTOR in the regulation of exosome release.…”

Section: Discussionmentioning

confidence: 99%

Dysregulated Autophagy and Lysosome Function Are Linked to Exosome Production by Micro‐RNA 155 in Alcoholic Liver Disease

et al. 2019

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“…Because the mTOR signaling pathway plays a vital role in the process of autophagy, it is important to study the relationship between the mTOR pathway and autophagy. The mTOR includes 2 functionally and biochemically distinct complexes, mTORC1 and mTORC2 . Evidence has shown that mTORC1, but not mTORC2, plays a vital role in the regulation of autophagy.…”

Section: Discussionmentioning

confidence: 99%

Thymoquinone inhibits the metastasis of renal cell cancer cells by inducing autophagy via AMPK/mTOR signaling pathway

et al. 2018

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Thymoquinone (TQ, 2‐methyl‐5‐isopropyl‐1,4‐benzoquinone), a bioactive constituent extracted from the seeds of Nigella sativa, has been proved to exert anti‐tumor efficiency in various cancers. Autophagy is a self‐digestion phenomenon, and its role in tumor formation and progression remains controversial. In the present study, we investigated the effects of TQ on renal cell cancer (RCC) cell lines (786‐O and ACHN) using wound healing assay, transwell assay and western blot analysis. We found that TQ effectively inhibited the metastatic capacity of RCC cells in vitro, which was also verified in a xenograft model. Meanwhile, we observed LC3 puncta and detected the expression of LC3 in TQ‐treated RCC cells, and then found that autophagy was induced by TQ in 786‐O and ACHN cell lines. In addition, TQ inhibited the migration and invasion as well as the EMT in RCC cells in an autophagy‐dependent manner. To further explore the underlying mechanism, we detected the AMPK/mTOR signaling pathway. The results indicated that TQ inhibited the metastasis of RCC cells by inducing autophagy via AMPK/mTOR signaling pathway. In conclusion, our findings provide a novel therapeutic strategy that aims at TQ‐induced autophagy in RCC treatment.

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“…Autophagy is regulated by a complex signaling network and mTOR pathway is the main regulatory mechanism for its suppression (Paquette et al, 2018[20]). We observed that exenatide was able to inhibit insulin stimulatory effect in a more significant way than liraglutide, proving to have a greater effect.…”

Section: Discussionmentioning

confidence: 99%