Cancer Cells Differentially Activate and Thrive on De Novo Lipid Synthesis Pathways in a Low-Lipid Environment

Abstract

Increased lipogenesis is a hallmark of a wide variety of cancers and is under intense investigation as potential antineoplastic target. Although brisk lipogenesis is observed in the presence of exogenous lipids, evidence is mounting that these lipids may adversely affect the efficacy of inhibitors of lipogenic pathways. Therefore, to fully exploit the therapeutic potential of lipid synthesis inhibitors, a better understanding of the interrelationship between de novo lipid synthesis and exogenous lipids and their respective role in cancer cell proliferation and therapeutic response to lipogenesis inhibitors is of critical importance. Here, we show that the proliferation of various cancer cell lines (PC3M, HepG2, HOP62 and T24) is attenuated when cultured in lipid-reduced conditions in a cell line-dependent manner, with PC3M being the least affected. Interestingly, all cell lines - lipogenic (PC3M, HepG2, HOP62) as well as non-lipogenic (T24) - raised their lipogenic activity in these conditions, albeit to a different degree. Cells that attained the highest lipogenic activity under these conditions were best able to cope with lipid reduction in term of proliferative capacity. Supplementation of the medium with very low density lipoproteins, free fatty acids and cholesterol reversed this activation, indicating that the mere lack of lipids is sufficient to activate de novo lipogenesis in cancer cells. Consequently, cancer cells grown in lipid-reduced conditions became more dependent on de novo lipid synthesis pathways and were more sensitive to inhibitors of lipogenic pathways, like Soraphen A and Simvastatin. Collectively, these data indicate that limitation of access to exogenous lipids, as may occur in intact tumors, activates de novo lipogenesis is cancer cells, helps them to thrive under these conditions and makes them more vulnerable to lipogenesis inhibitors. These observations have important implications for the design of new antineoplastic strategies targeting the cancer cell's lipid metabolism.

Omentum and bone marrow: how adipocyte‐rich organs create tumour microenvironments conducive for metastatic progression

“…In contrast, tumours such as ovarian cancers that grow in adipose-rich microenvironments have unconventional metabolism characterized by reduced lipogenesis and increased rates of β-oxidation (11). These observations are in line with other studies demonstrating that exogenous lipids sustain cancer cell survival when de novo lipogenesis is inhibited (33,34). It appears increasingly clear that instead of 'going through the trouble' of making their own fuel in order to proliferate, tumour cells growing in lipid-rich adipose environments take advantage of having these fuel molecules catered to them (27,35).…”

Endocytosis of very low-density lipoprotein particles: an unexpected mechanism for lipid acquisition by breast cancer cells

“…Attempts to remove LPL from the system proved challenging, as removing it from media incited shifts in the metabolic phenotype of cells. While some variations were observed among BC cell lines, removal of lipoproteins generally induced the expression of FA and cholesterol synthesis-related genes, mirroring the metabolic plasticity observed by Daniels and coworkers in prostate cancer cells [52].…”

“…Our findings have implications for the development of cancer therapeutics aimed at lipid metabolism. We and others have shown that cancer cells display increased sensitivity to FA synthesis inhibitors when cultured in lipid-reduced or lipoprotein-depleted media [5,[51][52][53]. It has likewise been demonstrated that cancer cells may adjust their relative reliance on FA synthesis vs. lipolysis/uptake in response to external factors, such as nutrient availability [52].…”

“…We previously showed that a majority of breast tumors display both LPL and CD36, and that provision of VLDL particles to BC cells (in the presence of LPL) stimulates cell growth and enables cells to evade the cytotoxic effects of FA synthesis inhibition [3]. These results, in concert with the observation that exogenous FFA can rescue cancer cells from the cytotoxic effects of FA synthesis inhibitors [5,[49][50][51][52][53], prompted the idea that BC cells might deploy LPL in a manner analogous to that of nonmalignant LPL-producing cells, such adipocytes or cardiomyocytes. Our findings support a model wherein LPL is bound to the cell surface, both in BC cell lines and in clinical BC tissue.…”

Probing the metabolic phenotype of breast cancer cells by multiple tracer stable isotope resolved metabolomics

“…Thus, the critical enzymes of fatty acid biosynthesis are commonly up regulated in cancer cells (Kuhajda 2000, Vazquez-Martin, Colomer et al 2008, Daniëls VW., Smans K. et al 2014). We have previously shown extensive de novo synthesis of complex lipids from glucose in the tamoxifen-resistant MCF-7 variant LCC2 cell line (Lane, Fan et al 2009).…”