Cited by 138Metabolism, Diabetes, and CancerCancer, Hypoxia, and MetabolismPI3K/AKT/mTOR signaling in cancer

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Serine Deprivation Enhances Antineoplastic Activity of Biguanides

Gravel, Simon-Pierre, Hulea, Laura, Toban, Nader, Birman, Elena, Blouin, Marie-José, Zakikhani, Mahvash, Zhao, Yunhua, Topisirovic, Ivan, St-Pierre, Julie, Pollak, Michael·2014·Cancer Research

DOI 10.1158/0008-5472.can-14-2643-t

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Abstract

Metformin, a biguanide widely used in the treatment of type II diabetes, clearly exhibits antineoplastic activity in experimental models and has been reported to reduce cancer incidence in diabetics. There are ongoing clinical trials to evaluate its antitumor properties, which may relate to its fundamental activity as an inhibitor of oxidative phosphorylation. Here, we show that serine withdrawal increases the antineoplastic effects of phenformin (a potent biguanide structurally related to metformin). Serine synthesis was not inhibited by biguanides. Instead, metabolic studies indicated a requirement for serine to allow cells to compensate for biguanide-induced decrease in oxidative phosphorylation by upregulating glycolysis. Furthermore, serine deprivation modified the impact of metformin on the relative abundance of metabolites within the citric acid cycle. In mice, a serine-deficient diet reduced serine levels in tumors and significantly enhanced the tumor growth–inhibitory actions of biguanide treatment. Our results define a dietary manipulation that can enhance the efficacy of biguanides as antineoplastic agents that target cancer cell energy metabolism. Cancer Res; 74(24); 7521–33. ©2014 AACR.

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Authors: Gravel, S.-P., Hulea, L., Toban, N., Birman, E., Blouin, M.-J., Zakikhani, M., Zhao, Y., Topisirovic, I., St-Pierre, J., & Pollak, M.
Affiliations: McGill University (CA)
Jewish General Hospital (CA)
2Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
1Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada.
3Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada.
ORCID: Gravel, Simon-Pierre
Hulea, Laura
Blouin, Marie-José
Venue: Cancer Research
Publisher: American Association for Cancer Research (AACR)
Published: 2014-12-14
Volume: 74
Issue: 24
Pages: 7521-7533
ISSN: 0008-5472 (ISSN-L)
1538-7445
DOI: 10.1158/0008-5472.can-14-2643-t
OpenAlex: W2016133306
Cited by: 138
References: 47
Citations by year: 2026: 3 · 2025: 10 · 2024: 13 · 2023: 14 · 2022: 15 · 2021: 24 · 2020: 15 · 2019: 13 · 2018: 8 · 2017: 7 · 2016: 11 · 2015: 5
FWCI: 3.14
Type: journal article
Language: en
Open access: closed
Locations: Cancer Research (publishedVersion)
PubMed (publishedVersion)
Funders: Canadian Institutes of Health Research (MOP115-195, FRN53888, 106603_1)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Keywords: biguanides, metformin, phenformin, anticancer activity, oxidative phosphorylation inhibition, glycolysis, cancer cell energy metabolism, tumor growth inhibition, dietary intervention
MeSH terms: Animals, Biguanides, Glycolysis, Humans, Metformin, Neoplasms, Oxidative Phosphorylation, Phenformin, Serine, Xenograft Model Antitumor Assays, Cell Line, Tumor, Mice

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Serine Deprivation Enhances Antineoplastic Activity of Biguanides

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