Sestrin2 integrates Akt and mTOR signaling to protect cells against energetic stress-induced death

Ben-Sahra, Issam; Dirat, Béatrice; Laurent, Kathiane; Puissant, Alexandre; Auberger, Patrick; Budanov, Andrei V.; Tanti, Jean‐François; Bost, Fréd́eric

doi:10.1038/cdd.2012.157

Cited by 135 publications

(112 citation statements)

References 38 publications

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“…Initially, the mechanism by which proteasome inhibition resulted in the disruption of mTORC1 remained vague, but recent studies using bortezomib as an autophagy inducer showing up-regulation of sestrin-2 (SESN2/Hi95) [122] have shed new light on this problem. SESN2 protects cells against oxidative and genotoxic stresses, and mediates the inhibition of mTOR [123]. Thus, the bortezomib-induced increase of SESN2 level leads to the inhibition of the main regulatory subunits of mTORC1 by a mechanism that requires interaction with AMPKa1 to mediate the phosphorylation of tuberous sclerosis2 (TSC2), an upstream mTOR inhibitor [119].…”

Section: Pi3k/akt/mtormentioning

confidence: 99%

Crosstalk between autophagy and proteasome protein degradation systems: possible implications for cancer therapy

Wójcik

2014

Folia Histochem Cytobiol.

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Abstract:The Ubiquitin-Proteasomes System (UPS) and autophagy, two main intracellular protein degradation pathways within the eukaryotic cells which were originally regarded as rather independent, seem to be very closely related. Proteasome inhibitors, including the multipathway inhibitor bortezomib, are drawing increased attention for their therapeutic potential in the treatment of chronic inflammation and cancer, especially tumours with a high degree of malignancy. The over-activation of autophagy induces cell death and may act as a powerful tumour-suppressing mechanism. However, autophagy, serving as an important mechanism to generate nutrients in time of cellular stresses, may directly contribute to the survival of cells treated with proteasome inhibitors, and in consequence, may decrease the effectiveness of therapy. Results of studies performed on several cancer cell lines demonstrated synergy between proteasome inhibitors and autophagy inhibitors. Those results became the base for ongoing clinical trials investigating autophagy inhibition in combination with anti-cancer therapies, including bortezomib. This review provides summary of the latest data on the functioning of the UPS and the mechanisms of autophagy. The new insights describing the main pathways of autophagy activation in response to UPS inhibition related to: (i) Unfolded Protein Response, (ii) PI3K/Akt/mTOR pathway, and (iii) formation of aggresomes, are discussed. It is concluded that concomitant inhibition of the two main cellular protein degradation systems may provide new therapeutic modalities for cancer treatment.

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Section: Pi3k/akt/mtormentioning

confidence: 99%

Crosstalk between autophagy and proteasome protein degradation systems: possible implications for cancer therapy

Wójcik

2014

Folia Histochem Cytobiol.

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“…In this process, long-lived proteins and whole organelles are sequestered in double-membraned vesicles, called autophagosomes, and digested. [16][17][18] Autophagy is a catabolic process through which cells digest their own components to provide energy and building blocks to maintain normal cellular function under unfavorable conditions, but it is also required, although at lower levels, under physiological conditions. 16,17,19 Interestingly, p53 appears to exhibit a dual role with respect to autophagy: whereas nuclear p53 induces autophagy by activation of the damage-regulated autophagy modulator (DRAM) gene, cytosolic p53 appears to inhibit autophagy by activation of the mTOR pathway.…”

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confidence: 99%

p73 regulates autophagy and hepatocellular lipid metabolism through a transcriptional activation of the ATG5 gene

Agostini

et al. 2013

Cell Death Differ

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p73, a member of the p53 tumor suppressor family, is involved in neurogenesis, sensory pathways, immunity, inflammation, and tumorigenesis. How p73 is able to participate in such a broad spectrum of different biological processes is still largely unknown. Here, we report a novel role of p73 in regulating lipid metabolism by direct transactivation of the promoter of autophagy-related protein 5 (ATG5), a gene whose product is required for autophagosome formation. Following nutrient deprivation, the livers of p73-deficient mice demonstrate a massive accumulation of lipid droplets, together with a low level of autophagy, suggesting that triglyceride hydrolysis into fatty acids is blocked owing to deficient autophagy (macrolipophagy). Compared with wild-type mice, mice functionally deficient in all the p73 isoforms exhibit decreased ATG5 expression and lower levels of autophagy in multiple organs. We further show that the TAp73a is the critical p73 isoform responsible for inducing ATG5 expression in a p53-independent manner and demonstrate that ATG5 gene transfer can correct autophagy and macrolipophagy defects in p73-deficient hepatocytes. These data strongly suggest that the p73-ATG5 axis represents a novel, key pathway for regulating lipid metabolism through autophagy. The identification of p73 as a major regulator of autophagy suggests that it may have an important role in preventing or delaying disease and aging by maintaining a homeostatic control. Cell Death and Differentiation (2013) 20, 1415-1424; doi:10.1038/cdd.2013.104; published online 2 August 2013 p73 belongs to the p53 family, a group of transcription factors that have key roles in the regulation of many cellular processes, such as apoptosis, cell cycle, and senescence, especially following DNA damage. 1-3 Whereas p53 is a tumor suppressor and often either deleted or mutated in tumors, p73 is rarely mutated; however, its expression is often deregulated in cancer. 4,5 In p73-deficient mice, unlike in p53-deficient mice, no increase in spontaneous tumorigenesis is observed. 6 It has been demonstrated, however, that p73, in the absence of DNA damage, has a role in neuronal differentiation and development. 6-9 Consequently, p73-deficient mice exhibit neurological defects and, even though no obvious deficiencies in lymphoid or granulocyte populations have been so far detected, such mice show deregulated inflammatory responses and senescence. 6,10 Because of splicing events occurring near the 3 0 end of the coding region and because of an alternative promoter located in the third intron of the gene, p73 exists as multiple protein variants. 11 The isoforms containing a transactivation (TA) domain (TAp73s) generally behave like p53 with respect to overlapping promoters and biological functions. 2,4 For instance, in contrast to p73-deficient mice, TAp73 knockout mice showed spontaneous as well as carcinogen-induced tumors, indicating that TAp73 is a tumor suppressor. 12 The alternative promoter also produces amino-terminal truncated DN isoforms, the so-called ...

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“…Some reports suggest that PI3K/AKT/p53 was activated by mammalian reovirus to inhibit virus replication/infection (37). A p53 target gene, Sesn2, is independent of p53 but requires the PI3K/AKT pathway to protect cells against oxidative and genotoxic stresses (38). Pacilitaxel can promote apoptosis and growth inhibition of human nasopharyngeal cancer cell line CNE2 by suppressing PI3K, p-AKT and increasing p53 level (39).…”

Section: Discussionmentioning

confidence: 99%

The co‑treatment of metformin with flavone synergistically induces apoptosis through inhibition of PI3K/AKT pathway in breast cancer cells

et al. 2018

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Abstract. Metformin, a widely used antidiabetic drug, exhibits anticancer effects which are mediated by the phosphatidylinositol 3-kinase (PI3K)/serine/threonine kinase (AKT) signaling pathway. However, its use in anticancer therapy combined with other natural products remains unclear. Flavone as the core structure of flavonoids has been demonstrated to induce cell apoptosis without causing serious side effect. Murine double minute X (MDMX) inhibits tumor suppressor gene p53 whose function is associated with the PI3K/AKT pathway. The results presented herein revealed that the combination of metformin and flavone significantly inhibited cell viability, and increased apoptosis of human breast cancer cells compared with metformin or flavone alone. The combination decreased the protein expression of MDMX, activated p53 through the PI3K/AKT signaling pathway, regulated p53 downstream target genes Bcl-2 apoptosis regulator, BCL2 associated X apoptosis regulator and cleaved caspase3, subsequently inducing apoptosis in MDA-MB-231 and MCF-7 breast cancer cells. These results indicated that dietary flavone may potentiate breast cancer cell apoptosis induced by metformin, and PI3K/AKT is involved in regulating MDMX/p53 signaling. This data suggests that dietary supplementary of flavone is a promising strategy for metformin mediated anticancer effects.

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Sestrin2 integrates Akt and mTOR signaling to protect cells against energetic stress-induced death

Cited by 135 publications

References 38 publications

Crosstalk between autophagy and proteasome protein degradation systems: possible implications for cancer therapy

Crosstalk between autophagy and proteasome protein degradation systems: possible implications for cancer therapy

p73 regulates autophagy and hepatocellular lipid metabolism through a transcriptional activation of the ATG5 gene

The co‑treatment of metformin with flavone synergistically induces apoptosis through inhibition of PI3K/AKT pathway in breast cancer cells

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