ReviewLipogenesis and lipolysis: The pathways exploited by the cancer cells to acquire fatty acids
Introduction
Cancer cells are characterized by their ability to divide more frequently than normal cells. Rapidly proliferating cancer cells exhibit increased demands for energy and macromolecules. To cope with these elevated requirements cancer cells undergo major metabolic modifications. Since the 1920s, it has been known that, in contrast to most normal tissues, cancer cells show avid glucose uptake and tend to convert glucose to lactate through the glycolytic pathway regardless of whether oxygen is present (aerobic glycolysis; Warburg Effect) [1]. Glucose metabolism via the glycolytic pathway provides not only energy, but also a carbon source for anabolic synthesis of critical biochemical precursors. It is now widely recognized that tumors frequently exhibit an increased ability to synthesize lipids [2], [3], and that this lipogenesis is tightly coupled to glucose metabolism.
Several lines of evidence suggest that activation of the de novo fatty acid (FA) synthesis pathway is required for carcinogenesis [4], [5], [6]. The FA synthesis pathway is extensively studied in the context of cancer biology and is currently thought to be the major pathway exploited by the cancer cells for the acquisition of FAs [5]. However, recent findings suggest that certain cancer cells/tissues can utilize both lipogenic and lipolytic pathways to acquire fatty acids that, in turn, promote cancer cell proliferation and survival [7], [8].
This review focuses on our current understanding of the roles of both the lipogenic and lipolytic pathways in mediating tumor growth and the therapeutic benefits that could possibly be achieved by targeting these pathways.
Section snippets
Fatty acids support various aspects of tumorigenesis
Fatty acids may contribute to cancer progression by multiple mechanisms (Fig. 1). The most widely discussed aspect of FA-biochemistry with respect to tumor biology is their role as building blocks for newly-synthesized membrane phospholipids. Large amounts of FAs are required to accommodate high rates of proliferation in cancer cells [5]. Cancer cells can acquire FAs through lipogenesis and/or lipolysis to support their growth and proliferation.
The source of FAs may determine the phospholipid
Lipogenesis versus lipolysis
Various tumor types display increased endogenous FA biosynthesis irrespective of extracellular lipid availability [21], whereas most normal cells, even those with comparatively high proliferation rates, preferentially use dietary/exogenous lipids for synthesis of new structural lipids [5], [21]. A few normal tissues such as adipocytes, hepatocytes, hormone-sensitive cells [22], the cycling endometrium, and fetal lung tissue [23] may have a very active FA-synthesis pathway. However, de novo FA
Therapeutic targeting of lipid metabolism for cancer treatment and prevention
Preceding attempts to exploit cancer FA requirements for therapeutic benefit mainly focused on de novo FA synthesis. Several research groups have shown that therapeutic targeting of various enzymes of this pathway such as ACLY, FASN and ACACA may result in tumor regression both in vitro and in vivo [5], [21], [25], [26], [27], [28]. Recent findings suggest that cancer cells can generate FAs via both lipogenic and lipolytic mechanisms that, in turn, support their proliferation and survival [7],
Acknowledgements
Work from the author’s laboratories was supported by Higher Education Commission, Pakistan (N. Zaidi). FWO Grant G.0691.12 (J.V. Swinnen), GOA Grant 11/009 (J.V. Swinnen), IAP7-32 Grant (J.V. Swinnen), NIH Grant RO1CA126618 (W.B. Kinlaw), Norris Cotton Cancer Center Prouty Grants (W.B. Kinlaw), NIH Training Grant DK07508 (N.B. Kuemmerle). The Program in Experimental and Molecular Medicine at the Geisel School of Medicine at Dartmouth (L. E. Lupien).
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