M(o)TOR of pseudo-hypoxic state in aging: Rapamycin to the rescue

Leontieva, Olga V.; Blagosklonny, Mikhail V.

doi:10.4161/cc.27973

Cited by 45 publications

(42 citation statements)

References 112 publications

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“…Whether decreased OX-PHOS contributes to the inhibition of ID8 proliferation by metformin remains to be determined. Interestingly, rapamycin, an inhibitor of mTOR pathway, showed similar effects as metformin in obese conditions and aging, however, rapamycin treatment ameliorates lactate production, which would indicate inhibition of glycolysis [88, 89], while metformin has been reported to induce glycolysis. Overall, these studies where by adipocytes contribute nutritionally to the microenvironment to influence the bioenergetics of tumor cell are supported by the paradigm of obesity (excess adiposity) being the provider of surplus nutrition which results in aggressive tumor growth and upregulation or inhibition of nutrition sensitive signaling pathways like mTOR and AMPK [28, 29].…”

Section: Discussionmentioning

confidence: 99%

Metformin limits the adipocyte tumor-promoting effect on ovarian cancer

et al. 2014

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Omental adipocytes promote ovarian cancer by secretion of adipokines, cytokines and growth factors, and acting as fuel depots. We investigated if metformin modulates the ovarian cancer promoting effects of adipocytes. Effect of conditioned media obtained from differentiated mouse 3T3L1 preadipoctes on the proliferation and migration of a mouse ovarian surface epithelium cancer cell line (ID8) was estimated. Conditioned media from differentiated adipocytes increased the proliferation and migration of ID8 cells, which was attenuated by metformin. Metformin inhibited adipogenesis by inhibition of key adipogenesis regulating transcription factors (CEBPα, CEBPß, and SREBP1), and induced AMPK. A targeted Cancer Pathway Finder RT-PCR (real-time polymerase chain reaction) based gene array revealed 20 up-regulated and 2 down-regulated genes in ID8 cells exposed to adipocyte conditioned media, which were altered by metformin. Adipocyte conditioned media also induced bio-energetic changes in the ID8 cells by pushing them into a highly metabolically active state; these effects were reversed by metformin. Collectively, metformin treatment inhibited the adipocyte mediated ovarian cancer cell proliferation, migration, expression of cancer associated genes and bio-energetic changes. Suggesting, that metformin could be a therapeutic option for ovarian cancer at an early stage, as it not only targets ovarian cancer, but also modulates the environmental milieu.

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Section: Discussionmentioning

confidence: 99%

Metformin limits the adipocyte tumor-promoting effect on ovarian cancer

et al. 2014

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“…Several potential processes have been proposed, including the regulation of the insulin/insulinlike growth factor, mTOR pathway, stem cells, and oxidative stress and reactive oxygen species. For instance, constitutive p53 activation may lead to the decline of self-renewal function of stem/progenitor cells and therefore contribute to aging [44], moreover its activation affects mTOR pathway, which drives conversion of "young" cells to senescent phenotype [45]. P53 levels increase with age, mirroring cumulative levels of stress [46], and inhibition of p53 results in an extension of fibroblast lifespan and osteoblastic differentiation [47].…”

Section: Mathematical Analysis and Modelingmentioning

confidence: 99%

Human Periosteal Derived Stem Cell Potential: The Impact of age

Ferretti

Lucarini

Andreoni

et al. 2014

Stem Cell Rev and Rep

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There is a great deal of interest in the understanding of possible age-related changes in Mesenchymal Stem Cells in view of their use for regenerative medicine applications. Given to the outmost standing of periosteum in bone biology and to probe data for a cell-based therapy promoting graft osseointegration in the elderly, we tried to identify specific aging markers or pattern of expression in human periosteal precursor cells. Immunohistochemical detection of Ki67 and p53, Nitric Oxide production and qRT- PCR of a selected gene panel for osteoblastic differentiation, bone remodeling and stemness were evaluated. We confirmed that both Ki67 and p53 are noteworthy indicators of senescence in human periosteal precursor cells and their expression significantly correlate with cell NO production. Moreover, cell age affects genes involved in bone remodeling, with a significant increase in interleukin-6 mRNA expression and receptor activator of nuclear factor kappa-B ligand/osteoprotegerin ratio. The analysis of mRNAs of genes involved in pluripotency regulation and self-renewal of stem cells, evidenced changes at least in part related to bone remodeling. We believe that this is the first study taking on age-related changes in human periosteal precursor cells, and paving the way toward new regenerative medicine strategies in bone aging and/or bone metabolic diseases.

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“…When the cell cycle is forcefully arrested, by DNA damaging agents and CDK inhibitors, then still active mTOR converts cycle arrest to senescence. [27][28][29][30][31][32][33][34][35][36][37][38] Any conditions that inhibit mTOR suppress geroconversion. 33,34,39,40 During geroconversion, levels of p-S6 are the same as its levels in proliferating cells.…”

Section: Mtor In Cellular Agingmentioning

confidence: 99%