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Dual mTORC1/C2 inhibitors suppress cellular geroconversion (a senescence program)
In proliferating cells, mTOR is active and promotes cell growth. When the cell cycle is arrested, then mTOR converts reversible arrest to senescence (geroconversion). Rapamycin and other rapalogs suppress geroconversion, maintaining quiescence instead. Here we showed that ATP-competitive kinase inhi...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4695114/ https://www.ncbi.nlm.nih.gov/pubmed/26177051 |
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author | Leontieva, Olga V. Demidenko, Zoya N. Blagosklonny, Mikhail V. |
author_facet | Leontieva, Olga V. Demidenko, Zoya N. Blagosklonny, Mikhail V. |
author_sort | Leontieva, Olga V. |
collection | PubMed |
description | In proliferating cells, mTOR is active and promotes cell growth. When the cell cycle is arrested, then mTOR converts reversible arrest to senescence (geroconversion). Rapamycin and other rapalogs suppress geroconversion, maintaining quiescence instead. Here we showed that ATP-competitive kinase inhibitors (Torin1 and PP242), which inhibit both mTORC1 and TORC2, also suppressed geroconversion. Despite inhibition of proliferation (in proliferating cells), mTOR inhibitors preserved re-proliferative potential (RP) in arrested cells. In p21-arrested cells, Torin 1 and PP242 detectably suppressed geroconversion at concentrations as low as 1-3 nM and 10-30 nM, reaching maximal gerosuppression at 30 nM and 300 nM, respectively. Near-maximal gerosuppression coincided with inhibition of p-S6K(T389) and p-S6(S235/236). Dual mTOR inhibitors prevented senescent morphology and hypertrophy. Our study warrants investigation into whether low doses of dual mTOR inhibitors will prolong animal life span and delay age-related diseases. A new class of potential anti-aging drugs can be envisioned. |
format | Online Article Text |
id | pubmed-4695114 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-46951142016-01-26 Dual mTORC1/C2 inhibitors suppress cellular geroconversion (a senescence program) Leontieva, Olga V. Demidenko, Zoya N. Blagosklonny, Mikhail V. Oncotarget Research Paper: Pathology In proliferating cells, mTOR is active and promotes cell growth. When the cell cycle is arrested, then mTOR converts reversible arrest to senescence (geroconversion). Rapamycin and other rapalogs suppress geroconversion, maintaining quiescence instead. Here we showed that ATP-competitive kinase inhibitors (Torin1 and PP242), which inhibit both mTORC1 and TORC2, also suppressed geroconversion. Despite inhibition of proliferation (in proliferating cells), mTOR inhibitors preserved re-proliferative potential (RP) in arrested cells. In p21-arrested cells, Torin 1 and PP242 detectably suppressed geroconversion at concentrations as low as 1-3 nM and 10-30 nM, reaching maximal gerosuppression at 30 nM and 300 nM, respectively. Near-maximal gerosuppression coincided with inhibition of p-S6K(T389) and p-S6(S235/236). Dual mTOR inhibitors prevented senescent morphology and hypertrophy. Our study warrants investigation into whether low doses of dual mTOR inhibitors will prolong animal life span and delay age-related diseases. A new class of potential anti-aging drugs can be envisioned. Impact Journals LLC 2015-07-27 /pmc/articles/PMC4695114/ /pubmed/26177051 Text en Copyright: © 2015 Leontieva et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper: Pathology Leontieva, Olga V. Demidenko, Zoya N. Blagosklonny, Mikhail V. Dual mTORC1/C2 inhibitors suppress cellular geroconversion (a senescence program) |
title | Dual mTORC1/C2 inhibitors suppress cellular geroconversion (a senescence program) |
title_full | Dual mTORC1/C2 inhibitors suppress cellular geroconversion (a senescence program) |
title_fullStr | Dual mTORC1/C2 inhibitors suppress cellular geroconversion (a senescence program) |
title_full_unstemmed | Dual mTORC1/C2 inhibitors suppress cellular geroconversion (a senescence program) |
title_short | Dual mTORC1/C2 inhibitors suppress cellular geroconversion (a senescence program) |
title_sort | dual mtorc1/c2 inhibitors suppress cellular geroconversion (a senescence program) |
topic | Research Paper: Pathology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4695114/ https://www.ncbi.nlm.nih.gov/pubmed/26177051 |
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