Role of mitochondrial uncoupling protein 2 in cancer cell resistance to gemcitabine
Open accessAbstract
Cancer cells exhibit an endogenous constitutive oxidative stress higher than that of normal cells, which renders tumours vulnerable to further reactive oxygen species (ROS) production. Mitochondrial uncoupling protein 2 (UCP2) can mitigate oxidative stress by increasing the influx of protons into the mitochondrial matrix and reducing electron leakage and mitochondrial superoxide generation. Here, we demonstrate that chemical uncouplers or UCP2 over-expression strongly decrease mitochondrial superoxide induction by the anticancer drug gemcitabine (GEM) and protect cancer cells from GEM-induced apoptosis. Moreover, we show that GEM IC(50) values well correlate with the endogenous level of UCP2 mRNA, suggesting a critical role for mitochondrial uncoupling in GEM resistance. Interestingly, GEM treatment stimulates UCP2 mRNA expression suggesting that mitochondrial uncoupling could have a role also in the acquired resistance to GEM. Conversely, UCP2 inhibition by genipin or UCP2 mRNA silencing strongly enhances GEM-induced mitochondrial superoxide generation and apoptosis, synergistically inhibiting cancer cell proliferation. These events are significantly reduced by the addition of the radical scavenger N-acetyl-l-cysteine or MnSOD over-expression, demonstrating a critical role of the oxidative stress. Normal primary fibroblasts are much less sensitive to GEM/genipin combination. Our results demonstrate for the first time that UCP2 has a role in cancer cell resistance to GEM supporting the development of an anti-cancer therapy based on UCP2 inhibition associated to GEM treatment.
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Low concentrations (1-5 μM) of FCCP promote cancer cell survival in response to topoisomerase inhibitors or gemcitabine, reducing apoptosis triggered by these molecules.
“Low concentrations (1–5 μM) of FCCP also promote cancer cell survival in response to topoisomerase inhibitors [178] or other chemotherapeutic agents, such as gemcitabine [179], reducing apoptosis triggered by these molecules.”
From Mitochondrial Uncoupling: A Key Controller of Biological Processes in Physiology and Diseases (2019) · cites this paper as [179]
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- Authors
- Dalla Pozza, E., Fiorini, C., Dando, I., Menegazzi, M., Sgarbossa, A., Costanzo, C., Palmieri, M., & Donadelli, M.
- Affiliations
- University of Verona (IT)
- Corresponding author
- Donadelli, Massimo
- Venue
- Biochimica et Biophysica Acta (BBA) - Molecular Cell Research
- Publisher
- Elsevier BV
- Published
- 2012-10
- Volume
- 1823
- Issue
- 10
- Pages
- 1856-1863
- ISSN
- 0167-4889 (ISSN-L)
- OpenAlex
- W1998564562
- Cited by
- 84
- References
- 36
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 4 · 2023: 4 · 2022: 3 · 2021: 6 · 2020: 9 · 2019: 8 · 2018: 5 · 2017: 8 · 2016: 10 · 2015: 8 · 2014: 5 · 2013: 5 · 2012: 3
- FWCI
- 2.70
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Biochimica et Biophysica Acta (BBA) - Molecular Cell Research (publishedVersion)
- PubMed (publishedVersion)
- INFM-OAR (INFN Catania) (submittedVersion, other-oa)
- Funders
- Associazione Italiana Ricerca Cancro
- Fondazione CariPaRo
- Joint Project of University of Verona
- Ministero dell'Istruzione, dell'Università e della Ricerca
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- mitochondrial uncoupling protein 2, UCP2, gemcitabine, drug resistance, oxidative stress, mitochondrial superoxide, apoptosis, genipin, N-acetylcysteine, manganese superoxide dismutase, reactive oxygen species, tumor cell proliferation, combination therapy
- MeSH terms
- Uncoupling Protein 2, Gemcitabine, Acetylcysteine, Deoxycytidine, Humans, Ion Channels, Neoplasms, Poly(ADP-ribose) Polymerases, RNA, Messenger, Superoxides, Superoxide Dismutase, Uncoupling Agents, Gene Expression Regulation, Neoplastic, Apoptosis, Drug Resistance, Neoplasm, Mitochondrial Proteins, Iridoids, Cell Line, Tumor, Cell Proliferation
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