Activation of the PIK3CA/AKT Pathway Suppresses Senescence Induced by an Activated RAS Oncogene to Promote Tumorigenesis
Open accessAbstract
Mutations in both RAS and the PTEN/PIK3CA/AKT signaling module are found in the same human tumors. PIK3CA and AKT are downstream effectors of RAS, and the selective advantage conferred by mutation of two genes in the same pathway is unclear. Based on a comparative molecular analysis, we show that activated PIK3CA/AKT is a weaker inducer of senescence than is activated RAS. Moreover, concurrent activation of RAS and PIK3CA/AKT impairs RAS-induced senescence. In vivo, bypass of RAS-induced senescence by activated PIK3CA/AKT correlates with accelerated tumorigenesis. Thus, not all oncogenes are equally potent inducers of senescence, and, paradoxically, a weak inducer of senescence (PIK3CA/AKT) can be dominant over a strong inducer of senescence (RAS). For tumor growth, one selective advantage of concurrent mutation of RAS and PTEN/PIK3CA/AKT is suppression of RAS-induced senescence. Evidence is presented that this new understanding can be exploited in rational development and targeted application of prosenescence cancer therapies.
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Several KRAS alleles had reduced comutation with NRAS and BRAF, and increased comutation with APC and PIK3CA.
“Several KRAS alleles had reduced comutation with NRAS and BRAF, and increased comutation with APC and PIK3CA”
From The origins and genetic interactions of KRAS mutations are allele- and tissue-specific (2021) · cites this paper as [45]
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- Authors
- Kennedy, A. L., Morton, J. P., Manoharan, I., Nelson, D. M., Jamieson, N. B., Pawlikowski, J. S., McBryan, T., Doyle, B., McKay, C., Oien, K. A., Enders, G. H., Zhang, R., Sansom, O. J., & Adams, P. D.
- Affiliations
- Fox Chase Cancer Center (US)
- Cancer Research UK Scotland Institute (GB)
- University of Glasgow (GB)
- Glasgow Royal Infirmary (GB)
- Corresponding author
- Sansom, Owen J.
- Adams, Peter D.
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2011-04
- Volume
- 42
- Issue
- 1
- Pages
- 36-49
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC3145340
- OpenAlex
- W2128124648
- Cited by
- 213
- References
- 58
- Citations by year
- 2026: 7 · 2025: 5 · 2024: 8 · 2023: 10 · 2022: 10 · 2021: 17 · 2020: 16 · 2019: 15 · 2018: 14 · 2017: 17 · 2016: 10 · 2015: 17 · 2014: 20 · 2013: 26 · 2012: 13
- FWCI
- 14.62
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion)
- Funders
- Cancer Research UK (C10652/A10250, 12481)
- National Institutes of Health
- National Institute of General Medical Sciences (R01GM062281)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- oncogenic Ras, cellular senescence, senescence bypass, carcinogenesis, PTEN, oncogene cooperation, PIK3CA mutation, Akt activation
- MeSH terms
- Aged, Animals, Cell Line, Transformed, Disease Models, Animal, Enzyme Activation, Female, Humans, Male, Mice, Transgenic, Middle Aged, Mutation, Neoplasms, Pancreatic Neoplasms, Genes, ras, Signal Transduction, Gene Expression Regulation, Neoplastic, Cellular Senescence, Mice, Knockout, Phosphatidylinositol 3-Kinases, Cell Proliferation, Proto-Oncogene Proteins c-akt, PTEN Phosphohydrolase, Mice, Class I Phosphatidylinositol 3-Kinases
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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