The diversity and breadth of cancer cell fatty acid metabolism

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Abstract

Tumor cellular metabolism exhibits distinguishing features that collectively enhance biomass synthesis while maintaining redox balance and cellular homeostasis. These attributes reflect the complex interactions between cell-intrinsic factors such as genomic-transcriptomic regulation and cell-extrinsic influences, including growth factor and nutrient availability. Alongside glucose and amino acid metabolism, fatty acid metabolism supports tumorigenesis and disease progression through a range of processes including membrane biosynthesis, energy storage and production, and generation of signaling intermediates. Here, we highlight the complexity of cellular fatty acid metabolism in cancer, the various inputs and outputs of the intracellular free fatty acid pool, and the numerous ways that these pathways influence disease behavior.

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Most cited references 332

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Understanding the Warburg effect: the metabolic requirements of cell proliferation.

Craig B Thompson, Matthew Vander Heiden, Lewis Cantley (2009)

In contrast to normal differentiated cells, which rely primarily on mitochondrial oxidative phosphorylation to generate the energy needed for cellular processes, most cancer cells instead rely on aerobic glycolysis, a phenomenon termed "the Warburg effect." Aerobic glycolysis is an inefficient way to generate adenosine 5'-triphosphate (ATP), however, and the advantage it confers to cancer cells has been unclear. Here we propose that the metabolism of cancer cells, and indeed all proliferating cells, is adapted to facilitate the uptake and incorporation of nutrients into the biomass (e.g., nucleotides, amino acids, and lipids) needed to produce a new cell. Supporting this idea are recent studies showing that (i) several signaling pathways implicated in cell proliferation also regulate metabolic pathways that incorporate nutrients into biomass; and that (ii) certain cancer-associated mutations enable cancer cells to acquire and metabolize nutrients in a manner conducive to proliferation rather than efficient ATP production. A better understanding of the mechanistic links between cellular metabolism and growth control may ultimately lead to better treatments for human cancer.

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The Emerging Hallmarks of Cancer Metabolism.

Natalya Pavlova, Craig B Thompson (2016)

Tumorigenesis is dependent on the reprogramming of cellular metabolism as both direct and indirect consequence of oncogenic mutations. A common feature of cancer cell metabolism is the ability to acquire necessary nutrients from a frequently nutrient-poor environment and utilize these nutrients to both maintain viability and build new biomass. The alterations in intracellular and extracellular metabolites that can accompany cancer-associated metabolic reprogramming have profound effects on gene expression, cellular differentiation, and the tumor microenvironment. In this Perspective, we have organized known cancer-associated metabolic changes into six hallmarks: (1) deregulated uptake of glucose and amino acids, (2) use of opportunistic modes of nutrient acquisition, (3) use of glycolysis/TCA cycle intermediates for biosynthesis and NADPH production, (4) increased demand for nitrogen, (5) alterations in metabolite-driven gene regulation, and (6) metabolic interactions with the microenvironment. While few tumors display all six hallmarks, most display several. The specific hallmarks exhibited by an individual tumor may ultimately contribute to better tumor classification and aid in directing treatment.

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ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition.

Sebastian Doll, Bettina Proneth, Yulia Tyurina … (2017)

Ferroptosis is a form of regulated necrotic cell death controlled by glutathione peroxidase 4 (GPX4). At present, mechanisms that could predict sensitivity and/or resistance and that may be exploited to modulate ferroptosis are needed. We applied two independent approaches-a genome-wide CRISPR-based genetic screen and microarray analysis of ferroptosis-resistant cell lines-to uncover acyl-CoA synthetase long-chain family member 4 (ACSL4) as an essential component for ferroptosis execution. Specifically, Gpx4-Acsl4 double-knockout cells showed marked resistance to ferroptosis. Mechanistically, ACSL4 enriched cellular membranes with long polyunsaturated ω6 fatty acids. Moreover, ACSL4 was preferentially expressed in a panel of basal-like breast cancer cell lines and predicted their sensitivity to ferroptosis. Pharmacological targeting of ACSL4 with thiazolidinediones, a class of antidiabetic compound, ameliorated tissue demise in a mouse model of ferroptosis, suggesting that ACSL4 inhibition is a viable therapeutic approach to preventing ferroptosis-related diseases.

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Author and article information

Contributors

Andrew J. Hoy:

ORCID: http://orcid.org/0000-0003-3922-1137

andrew.hoy@sydney.edu.au

Journal

Journal ID (nlm-ta): Cancer Metab

Journal ID (iso-abbrev): Cancer Metab

Title: Cancer & Metabolism

Publisher: BioMed Central (London )

ISSN (Electronic): 2049-3002

Publication date (Electronic): 7 January 2021

Publication date PMC-release: 7 January 2021

Publication date Collection: 2021

Volume: 9

Electronic Location Identifier: 2

Affiliations

[1 ]GRID grid.1013.3, ISNI 0000 0004 1936 834X, Discipline of Physiology, School of Medical Sciences, Charles Perkins Centre, Faculty of Medicine and Health, , The University of Sydney, ; Sydney, NSW Australia

[2 ]GRID grid.4991.5, ISNI 0000 0004 1936 8948, Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, , University of Oxford, Churchill Hospital, ; Oxford, UK

[3 ]GRID grid.1010.0, ISNI 0000 0004 1936 7304, Adelaide Medical School and Freemasons Foundation Centre for Men’s Health, , University of Adelaide, ; Adelaide, SA Australia

[4 ]GRID grid.430453.5, ISNI 0000 0004 0565 2606, South Australian Health and Medical Research Institute, ; Adelaide, SA Australia

Author information

Andrew J. Hoy http://orcid.org/0000-0003-3922-1137

Article

Publisher ID: 237

DOI: 10.1186/s40170-020-00237-2

PMC ID: 7791669

PubMed ID: 33413672

SO-VID: 1bf8f4f0-8610-4578-aa7e-7f55a6726b5f

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 3 September 2020

Date accepted : 16 December 2020

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100008719, Movember Foundation;

Award ID: MRTA3

Award Recipient : Lisa M. Butler Andrew J. Hoy

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Keywords: fatty acid,lipid,cellular membrane,de novo synthesis,lipid droplets,mitochondria,peroxisome,oxidation

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Keywords: fatty acid, lipid, cellular membrane, de novo synthesis, lipid droplets, mitochondria, peroxisome, oxidation

The diversity and breadth of cancer cell fatty acid metabolism

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Abstract

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Cancer Metabolism

Most cited references 332

Understanding the Warburg effect: the metabolic requirements of cell proliferation.

The Emerging Hallmarks of Cancer Metabolism.

ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition.

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