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.

Keywords: Cancer; Fatty acid synthase; Fatty acid synthesis; Lipogenesis; Lipolysis; Lipoprotein lipase.

Figure 1. Fatty acids promote various aspects of tumor cell development, progression and survival

Fatty acids provide the cancer cells with membrane building blocks, signaling molecules and energy source that supports their rapid proliferation and survival. (See text for more details)

Figure 2. Fatty acid acquisition by tumors

Glucose and glutamine supply carbon that enzymes of lipogenesis, including fatty acid synthase (FASN), use to synthesize FA. Alternatively, exogenous FA may be acquired by extracellular lipolysis TG from the TG-rich lipoproteins (TGRL) using the secreted enzyme lipoprotein lipase (LPL) bound to a heparin-like heparan sulfate proteoglycan motif on the luminal surface of vascular epithelium. Resultant free FAs enter the cancer cell via CD36, the FA uptake channel. This is the mechanism used by normal adipose and striated muscle cells. The presence of a heparin-releasable pool of LPL and the HSPG motif on the surface of tumor cells raises the novel possibility that malignant cells may decorate their surface with the enzyme, rather than simply secreting it. In this speculative arrangement LPL tumor cell surface-associated LPL could mediate extracellular hydrolysis. Alternatively, LPL could facilitate endocytosis of lipoproteins by serving as a non-enzymatic bridge between the cell surface heparan sulfate binding site and the lipoprotein.