Targeting a Sirt5-Positive Subpopulation Overcomes Multidrug Resistance in Wild-Type Kras Colorectal Carcinomas
Open accessAbstract
A major obstacle for successful management of patients with colorectal carcinoma (CRC) is resistance to anti-cancer cytotoxic treatments. Here, we identified a mechanism of multidrug resistance in wild-type Kras CRCs based on the survival of a cell subpopulation characterized by Sirt5 expression. Sirt5+ cells in wild-type Kras CRCs are resistant to either chemotherapeutic agents or cetuximab and serve as a reservoir for recurrence. Sirt5 demalonylates and inactivates succinate dehydrogenase complex subunit A (SDHA), leading to an accumulation of the oncometabolite succinate. Succinate binds to and activates a reactive oxygen species-scavenging enzyme, thioredoxin reductase 2 (TrxR2), to confer chemotherapy resistance. In contrast, Sirt5+ cells exhibit an elevated succinate-to-aKG ratio that inhibits aKG-dependent dioxygenases to maintain cetuximab resistance. Our findings suggest that Sirt5 inhibitors in combination with chemotherapeutic agents and/or cetuximab may represent a therapeutic strategy for CRC patients harboring wild-type Kras.
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Sirt5-positive CRCs develop cetuximab resistance due to an elevated succinate-to-ketoglutarate (αKG) ratio, which inhibits αKG-dependent dioxygenases.
“Sirt5-positive CRCs develop cetuximab resistance due to an elevated succinate-to-ketoglutarate (αKG) ratio, which inhibits αKG-dependent dioxygenases [134].”
From Resistance to anti-EGFR therapies in metastatic colorectal cancer: underlying mechanisms and reversal strategies (2021) · cites this paper as [134]
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References 36 · Cited by 56
- Authors
- Du, Z., Liu, X., Chen, T., Gao, W., Wu, Z., Hu, Z., Wei, D., Gao, C., & Li, Q.
- Affiliations
- Shanghai Medical College of Fudan University (CN)
- Fudan University (CN)
- Second Military Medical University (CN)
- People's Liberation Army No. 150 Hospital (CN)
- Corresponding author
- Li, QingQuan
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2018-03
- Volume
- 22
- Issue
- 10
- Pages
- 2677-2689
- ISSN
- 2211-1247 (ISSN-L)
- OpenAlex
- W2792332350
- Cited by
- 56
- References
- 36
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 5 · 2023: 8 · 2022: 10 · 2021: 9 · 2020: 7 · 2019: 10 · 2018: 3
- FWCI
- 2.73
- Type
- journal article
- Language
- en
- Update notices
- erratum (2018-06-26)
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Nature Science Foundation of China (81372350, 81172099, 81572886)
- Topics
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- SIRT5, multidrug resistance, colorectal cancer, KRAS wild-type, succinate accumulation, TXNRD2, reactive oxygen species scavenging, cetuximab resistance, chemoresistance, tumor recurrence
- MeSH terms
- Cetuximab, DNA Demethylation, Animals, Cell Survival, Female, Histones, Humans, Ketoglutaric Acids, Mice, Inbred BALB C, Mice, Nude, Neoplasm Recurrence, Local, Succinates, Colorectal Neoplasms, Proto-Oncogene Proteins p21(ras), Drug Resistance, Multiple, Drug Resistance, Neoplasm, Sirtuins, Electron Transport Complex II, Cell Line, Tumor, Thioredoxin Reductase 2
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