Glutathione biosynthesis is a metabolic vulnerability in PI(3)K/Akt-driven breast cancer
Open accessAbstract
Cancer cells often select for mutations that enhance signalling through pathways that promote anabolic metabolism. Although the PI(3)K/Akt signalling pathway, which is frequently dysregulated in breast cancer, is a well-established regulator of central glucose metabolism and aerobic glycolysis, its regulation of other metabolic processes required for tumour growth is not well defined. Here we report that in mammary epithelial cells, oncogenic PI(3)K/Akt stimulates glutathione (GSH) biosynthesis by stabilizing and activating NRF2 to upregulate the GSH biosynthetic genes. Increased NRF2 stability is dependent on the Akt-mediated accumulation of p21(Cip1/WAF1) and GSK-3β inhibition. Consistently, in human breast tumours, upregulation of NRF2 targets is associated with PI(3)K pathway mutation status and oncogenic Akt activation. Elevated GSH biosynthesis is required for PI(3)K/Akt-driven resistance to oxidative stress, initiation of tumour spheroids, and anchorage-independent growth. Furthermore, inhibition of GSH biosynthesis with buthionine sulfoximine synergizes with cisplatin to selectively induce tumour regression in PI(3)K pathway mutant breast cancer cells, both in vitro and in vivo. Our findings provide insight into GSH biosynthesis as a metabolic vulnerability associated with PI(3)K pathway mutant breast cancers.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Genetic or pharmacological inhibition of glutathione synthesis results in ROS accumulation and impedes cancer initiation and cell proliferation.
“Several screens for small-molecules that selectively kill transformed cells have identified compounds that reduce glutathione levels (Dolma et al., 2003; Raj et al., 2011; Trachootham et al., 2006), and genetic or pharmacological inhibition of glutathione synthesis results in ROS accumulation and impedes cancer initiation and cell proliferation (Harris et al., 2015; Lien et al., 2016).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Lien et al., 2016
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
The citation lists haven’t been fetched yet
References 42 · Cited by 249
- Authors
- Lien, E. C., Lyssiotis, C. A., Juvekar, A., Hu, H., Asara, J. M., Cantley, L. C., & Toker, A.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- University of Michigan (US)
- Weill Cornell Medicine (US)
- Corresponding author
- Toker, Alex
- Venue
- Nature Cell Biology
- Published
- 2016-04-18
- Volume
- 18
- Issue
- 5
- Pages
- 572-578
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- PMC
- PMC4848114
- OpenAlex
- W2336310263
- Cited by
- 249
- References
- 42
- Citations by year
- 2026: 15 · 2025: 22 · 2024: 19 · 2023: 21 · 2022: 27 · 2021: 33 · 2020: 43 · 2019: 25 · 2018: 20 · 2017: 21 · 2016: 2 · 2015: 1
- FWCI
- 11.71
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Funders
- National Cancer Institute (R01CA177910, P01CA120964, P30CA046592, P30CA006516)
- National Institute of General Medical Sciences (R01GM041890)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- glutathione synthesis, PI3K/Akt signaling, breast cancer, NRF2 stabilization, p21, GSK3β, oxidative stress resistance, tumor spheroids, anchorage-independent growth, buthionine sulfoximine, cisplatin combination therapy, metabolic vulnerability, PI3K pathway mutations
- MeSH terms
- Breast Neoplasms, Cisplatin, Female, Glutathione, Humans, Mutation, Signal Transduction, Oxidative Stress, Spheroids, Cellular, Buthionine Sulfoximine, Phosphatidylinositol 3-Kinases, Cell Line, Tumor, Proto-Oncogene Proteins c-akt, NF-E2-Related Factor 2, Biosynthetic Pathways
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.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
