Hypoxia suppresses conversion from proliferative arrest to cellular senescence
Open accessAbstract
Unlike reversible quiescence, cellular senescence is characterized by a large flat cell morphology, β-gal staining and irreversible loss of regenerative (i.e., replicative) potential. Conversion from proliferative arrest to irreversible senescence, a process named geroconversion, is driven in part by growth-promoting pathways such as mammalian target of rapamycin (mTOR). During cell cycle arrest, mTOR converts reversible arrest into senescence. Inhibitors of mTOR can suppress geroconversion, maintaining quiescence instead. It was shown that hypoxia inhibits mTOR. Therefore, we suggest that hypoxia may suppress geroconversion. Here we tested this hypothesis. In HT-p21-9 cells, expression of inducible p21 caused cell cycle arrest without inhibiting mTOR, leading to senescence. Hypoxia did not prevent p21 induction and proliferative arrest, but instead inhibited the mTOR pathway and geroconversion. Exposure to hypoxia during p21 induction prevented senescent morphology and loss of regenerative potential, thus maintaining reversible quiescence so cells could restart proliferation after switching p21 off. Suppression of geroconversion was p53- and HIF-1-independent, as hypoxia also suppressed geroconversion in cells lacking functional p53 and HIF-1α. Also, in normal fibroblasts and retinal cells, hypoxia inhibited the mTOR pathway and suppressed senescence caused by etoposide without affecting DNA damage response, p53/p21 induction and cell cycle arrest. Also hypoxia suppressed geroconversion in cells treated with nutlin-3a, a nongenotoxic inducer of p53, in cell lines susceptible to nutlin-3a-induced senescence (MEL-10, A172, and NKE). Thus, in normal and cancer cell lines, hypoxia suppresses geroconversion caused by diverse stimuli. Physiological and clinical implications of the present findings are discussed.
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Hypoxia prevents cultured cells from senescing.
“Because hypoxia has been reported to prevent cultured cells from senescing (Leontieva et al., 2012; Parinello, 2003”
From In Vitro Expansion of Primary Human Hepatocytes with Efficient Liver Repopulation Capacity (2018) · cites this paper as Leontieva et al., 2012
mTOR can toggle the decision between quiescence and senescence.
“It has also been suggested that the mammalian target of rapamycin (mTOR) can toggle the decision between quiescence and senescence (Korotchkina et al., 2010; Leontieva et al., 2012).”
From CDK4/6 Inhibitors: The Mechanism of Action May Not Be as Simple as Once Thought (2018) · cites this paper as Leontieva et al., 2012
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- Authors
- Leontieva, O. V., Natarajan, V., Demidenko, Z. N., Burdelya, L. G., Gudkov, A. V., & Blagosklonny, M. V.
- Affiliations
- Roswell Park Comprehensive Cancer Center (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2012-07-30
- Volume
- 109
- Issue
- 33
- Pages
- 13314-13318
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3421205
- OpenAlex
- W2058045514
- Cited by
- 169
- References
- 55
- Citations by year
- 2026: 6 · 2025: 2 · 2024: 8 · 2023: 6 · 2022: 7 · 2021: 10 · 2020: 8 · 2019: 5 · 2018: 9 · 2017: 12 · 2016: 14 · 2015: 15 · 2014: 31 · 2013: 28 · 2012: 8
- FWCI
- 17.58
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- cellular senescence, hypoxia, mTOR signaling, p21, cell cycle arrest, quiescence, p53-independent senescence, Nutlin-3a, replicative potential, fibroblasts, retinal cells
- MeSH terms
- Cell Line, Epithelial Cells, Etoposide, Fibroblasts, Humans, Imidazoles, Piperazines, Cell Hypoxia, Tumor Suppressor Protein p53, Cellular Senescence, Cell Proliferation, Cyclin-Dependent Kinase Inhibitor p21, Hypoxia-Inducible Factor 1, alpha Subunit
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