Lipogenesis and lipolysis: The pathways exploited by the cancer cells to acquire fatty acids

Abstract

One of the most important metabolic hallmarks of cancer cells is enhanced lipogenesis. Depending on the tumor type, tumor cells synthesize up to 95% of saturated and mono-unsaturated fatty acids (FA) de novo in spite of sufficient dietary lipid supply. This lipogenic conversion starts early when cells become cancerous and further expands as the tumor cells become more malignant. It is suggested that activation of FA synthesis is required for carcinogenesis and for tumor cell survival. These observations suggest that the enzymes involved in FA synthesis would be rational therapeutic targets for cancer treatment. However, several recent reports have shown that the anti-tumor effects, following inhibition of endogenous FA synthesis in cancer cell lines may be obviated by adding exogenous FAs. Additionally, high intake of dietary fat is reported to be a potential risk factor for development and poor prognosis for certain cancers. Recently it was reported that breast and liposarcoma tumors are equipped for both de novo fatty acid synthesis pathway as well as LPL-mediated extracellular lipolysis. These observations indicate that lipolytically acquired FAs may provide an additional source of FAs for cancer. This review focuses on our current understanding of lipogenic and lipolytic pathways in cancer cell progression.

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.