Cancer metabolism: current perspectives and future directions
Open accessAbstract
Cellular metabolism influences life and death decisions. An emerging theme in cancer biology is that metabolic regulation is intricately linked to cancer progression. In part, this is due to the fact that proliferation is tightly regulated by availability of nutrients. Mitogenic signals promote nutrient uptake and synthesis of DNA, RNA, proteins and lipids. Therefore, it seems straight-forward that oncogenes, that often promote proliferation, also promote metabolic changes. In this review we summarize our current understanding of how 'metabolic transformation' is linked to oncogenic transformation, and why inhibition of metabolism may prove a cancer's 'Achilles' heel'. On one hand, mutation of metabolic enzymes and metabolic stress sensors confers synthetic lethality with inhibitors of metabolism. On the other hand, hyperactivation of oncogenic pathways makes tumors more susceptible to metabolic inhibition. Conversely, an adequate nutrient supply and active metabolism regulates Bcl-2 family proteins and inhibits susceptibility to apoptosis. Here, we provide an overview of the metabolic pathways that represent anti-cancer targets and the cell death pathways engaged by metabolic inhibitors. Additionally, we will detail the similarities between metabolism of cancer cells and metabolism of proliferating cells.
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A glycolytic switch involving differential expression of pyruvate kinase isoforms and stabilization of HIF1α upregulates rate-limiting enzymes within branching pathways of glycolysis, ensuring that glycolytic intermediates are free to take part in diverse biosynthetic reactions essential for increased proliferation.
“A glycolytic switch involving differential expression of pyruvate kinase isoforms and stabilization of HIF1α upregulates rate-limiting enzymes within branching pathways of glycolysis, ensuring that glycolytic intermediates are free to take part in diverse biosynthetic reactions that are essential for increased proliferation (196).”
From Metabolic Flexibility as an Adaptation to Energy Resources and Requirements in Health and Disease (2018) · cites this paper as [196]
Alternative glycolytic branching pathways include the PPP using glucose-6-phosphate, hexosamine biosynthesis using fructose-6-phosphate, phospholipid biosynthesis using dihydroxyacetone phosphate, and glycine and serine biosynthesis using 3-phosphoglycerate.
“These alternative pathways include the PPP using glucose-6-phosphate, hexosamine biosynthesis using fructose-6-phosphate, phospholipid biosynthesis using dihydroxyacetone phosphate, and glycine and serine biosynthesis using 3-phosphoglycerate.”
From Metabolic Flexibility as an Adaptation to Energy Resources and Requirements in Health and Disease (2018) · cites this paper as [196]
Increased glucose uptake and metabolism in cancer is very often mediated by the oncogenic signaling protein Ras, which activates the PI3K/Akt pathway; PI3K/Akt signaling increases GLUT1 expression and translocation to the cell surface and enhances HK and phosphofructokinase activity, capturing glucose and increasing glycolytic flux.
“Increased glucose uptake and metabolism is very often mediated by the oncogenic signaling protein Ras, which activates the PI3K/Akt pathway. PI3K/Akt signaling increases the expression of GLUT1 and its translocation to the cell surface, and enhances HK and phosphofructokinase activity, thus capturing glucose and increasing glycolytic flux (196).”
From Metabolic Flexibility as an Adaptation to Energy Resources and Requirements in Health and Disease (2018) · cites this paper as [196]
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References 120 · Cited by 385
- Authors
- Muñoz-Pinedo, C., El Mjiyad, N., & Ricci, J.-E.
- Affiliations
- Inserm (FR)
- ORCID
- Ricci, J-E
- Venue
- Cell Death & Disease
- Published
- 2012-01-12
- Volume
- 3
- Issue
- 1
- Pages
- e248-e248
- ISSN
- 2041-4889 (ISSN-L)
- PMC
- PMC3270265
- OpenAlex
- W2078693224
- Cited by
- 385
- References
- 120
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 36 · 2023: 11 · 2022: 11 · 2021: 16 · 2020: 35 · 2019: 25 · 2018: 26 · 2017: 46 · 2016: 40 · 2015: 47 · 2014: 42 · 2013: 33 · 2012: 9
- FWCI
- 3.13
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc-nd
- www.springer.com/tdm (unspecified)
- Locations
- Cell Death and Disease (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- RECERCAT (Consorci de Serveis Universitaris de Catalunya) (publishedVersion, other-oa)
- Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona) (submittedVersion, cc-by-nc-sa)
- Funders
- Association pour la Recherche sur le Cancer
- Agence Nationale de la Recherche (RD06/0020, ANR-09-JCJC-0003)
- Institut National de la Santé et de la Recherche Médicale (RD06/0020)
- Centre Hospitalier Universitaire de Nice
- Instituto de Salud Carlos III (RD06/0020)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- cancer metabolism, metabolic transformation, oncogenic transformation, metabolic inhibitors, synthetic lethality, nutrient availability, oncogenes, Bcl-2 family proteins, apoptosis, cell death pathways, anticancer drug targets, tumor cell proliferation
- MeSH terms
- Animals, Cell Communication, Cell Transformation, Neoplastic, Glucose, Humans, Mitochondria, Neoplasms, Oncogenes, Signal Transduction, Gene Expression Regulation, Neoplastic, Apoptosis, Proto-Oncogene Proteins c-bcl-2, Biomedical Research, Cell Proliferation, Mice, Metabolic Networks and Pathways
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