Dual mTORC1/C2 inhibitors: gerosuppressors with potential anti-aging effect

Sousa‐Victor, Pedro; García‐Prat, Laura; Muñoz‐Cánoves, Pura

doi:10.18632/oncotarget.5563

Cited by 18 publications

(8 citation statements)

References 17 publications

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“…Inactivation of the TORC1 pathway also causes cells to arrest in G1 (Sousa-Victor et al 2015), but cells neither increase in size during the arrest nor undergo senescence (Sousa-Victor et al 2015;Kucheryavenko et al 2019). RPE1-hTERT cells were arrested in G1 by treating them with 5 μM of the mTOR kinase inhibitor torin1, for 24 hours ( Figure 2F).…”

Section: Prolonged G1 Arrest Associated With Cell Size Increase Elicimentioning

confidence: 99%

Aneuploid cells activate NF-κB to promote their immune clearance by NK cells

Wang

Vigano'

Ben‐David

et al. 2020

Preprint

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SummaryThe immune system plays a major role in the protection against cancer. Identifying and characterizing the pathways mediating this immune surveillance is thus critical for understanding how cancer cells are recognized and eliminated. We previously found that untransformed cells that had undergone senescence due to highly abnormal karyotypes are eliminated by Natural Killer (NK) cells in vitro. Here we show that this is also true for aneuploid untransformed cells that had not lost their ability to proliferate. Their elimination by NK cells, like that of aneuploid senescent cells, is predominantly mediated by non-cell autonomous mechanisms. Our data further indicate that NF-κB signaling in aneuploid cells is central to eliciting this immune response. Inactivating NF-κB abolishes NK-cell mediated clearance in aneuploid cells in vitro. In cancer cell lines, NF-κB signaling correlates with degree of aneuploidy, raising the possibility that aneuploidy-induced immune recognition is partially retained in cancer.

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Section: Prolonged G1 Arrest Associated With Cell Size Increase Elicimentioning

confidence: 99%

Aneuploid cells activate NF-κB to promote their immune clearance by NK cells

Wang

Vigano'

Ben‐David

et al. 2020

Preprint

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“…When IPTG and rapamycin are washed out, cells re-proliferate [ 68 - 73 , 77 ]. Recently, we have shown that Torin 1 and PP242 suppresses geroconversion, prevent-ing senescent morphology and loss of RPP [ 78 , 79 ]. In agreement, reversal of senescent phenotype was shown by another pan-mTOR inhibitor, AZD8085 [ 80 ].…”

Section: Introductionmentioning

confidence: 99%

Gerosuppression by pan-mTOR inhibitors

Leontieva

Blagosklonny

2016

Aging

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Rapamycin slows organismal aging and delays age-related diseases, extending lifespan in numerous species. In cells, rapamycin and other rapalogs such as everolimus suppress geroconversion from quiescence to senescence. Rapamycin inhibits some, but not all, activities of mTOR. Recently we and others demonstrated that pan-mTOR inhibitors, known also as dual mTORC1/C2 inhibitors, suppress senescent phenotype. As a continuation of these studies, here we investigated in detail a panel of pan-mTOR inhibitors, to determine their optimal gerosuppressive concentrations. During geroconversion, cells become hypertrophic and flat, accumulate lysosomes (SA-beta-Gal staining) and lipids (Oil Red staining) and lose their re-proliferative potential (RPP). We determined optimal gerosuppressive concentrations: Torin1 (30 nM), Torin 2 (30 nM), AZD8055 (100 nM), PP242 (300 nM), both KU-006379 and GSK1059615 (1000 nM). These agents decreased senescence-associated hypertrophy with IC50s: 20, 18, 15, 200 and 400 nM, respectively. Preservation of RPP by pan-mTOR inhibitors was associated with inhibition of the pS6K/pS6 axis. Inhibition of rapamycin-insensitive functions of mTOR further contributed to anti-hypertrophic and cytostatic effects. Torin 1 and PP242 were more “rapamycin-like” than Torin 2 and AZD8055. Pan-mTOR inhibitors were superior to rapamycin in suppressing hypertrophy, senescent morphology, Oil Red O staining and in increasing so-called “chronological life span (CLS)”. We suggest that, at doses lower than anti-cancer concentrations, pan-mTOR inhibitors can be developed as anti-aging drugs.

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“…Activation of the PI3K/AKT/mTOR pathway independent of PTEN loss is also implicated in replicative senescence, and inhibition of mTOR was shown to prevent ageing in different experimental in vivo models [ 3 - 6 ]. Interestingly, rapamycin and metformin two potent mTOR inhibitors, suppress geroconversion, prevent cancer and have minor side effects when administered long-term in anti-aging doses [ 7 - 22 ]. Activation of the PI3K/AKT pathway is also implicated in UV induced cellular senescence, a phenomenon known as photo ageing.…”

Section: Introductionmentioning

confidence: 99%

Identification of Salvia haenkei as gerosuppressant agent by using an integrated senescence-screening assay

Matić

Chen

Bisio

et al. 2016

Aging

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Cellular senescence is a stable cell cycle arrest that is the causative process of aging. The PI3K/AKT/mTOR pathway is implicated in the control of cellular senescence and inhibitors of this pathway have been successfully used for life span prolongation experiments in mammals. PTEN is the major regulator of the PI3K/AKT/mTOR pathway and loss of PTEN promotes a senescence response termed PICS. Here we report a novel-screening assay, for the identification of compounds that block different types of senescence response. By testing a library of more than 3000 natural and chemical compounds in PTEN deficient cells we have found that an extract from Salvia haenkei (SH), a native plant of Bolivia is a potent inhibitor of PICS. SH also decreases replicative and UV-mediated senescence in human primary fibroblasts and in a model of in vitro reconstructed human epidermis. Mechanistically, SH treatment affects senescence driven by UV by interfering with IL1-ɑ signalling. Pre-clinical and clinical testing of this extract by performing toxicity and irritability evaluation in vitro also demonstrate the safety of SH extract for clinical use as anti-aging skin treatment.

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Dual mTORC1/C2 inhibitors: gerosuppressors with potential anti-aging effect

Cited by 18 publications

References 17 publications

Aneuploid cells activate NF-κB to promote their immune clearance by NK cells

Aneuploid cells activate NF-κB to promote their immune clearance by NK cells

Gerosuppression by pan-mTOR inhibitors

Identification of Salvia haenkei as gerosuppressant agent by using an integrated senescence-screening assay

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