ABSTRACT
We previously described the expression of CD36 and lipoprotein lipase (LPL) by breast cancer (BC) cells and tissues, and the growth-promoting effect of very low-density lipoprotein (VLDL) supplementation observed in BC cell lines only in the presence of LPL. We now describe the deployment of LPL by BC cells. Our data support a model in which LPL is bound to a heparin-like heparan sulfate proteoglycan motif on the BC cell surface and acts in concert with the VLDL receptor to rapidly internalize intact lipoproteins via receptor-mediated endocytosis. We further observe substantial alterations in gene expression programs related to pathways for lipid acquisition (synthesis vs. uptake) in response to each the availability of exogenous triglyceride in tissue culture media and LPL expression status. Current literature emphasizes de novo fatty acid synthesis as the paramount mechanism for lipid acquisition by cancer cells. Our findings indicate that exogenous lipid uptake can serve as an important method of lipid acquisition for cancer cells, alongside de novo lipogenesis, and that the relative reliance on these two modes of lipid acquisition may vary among different BC cell lines and in response to nutrient availability. This concept has obvious implications for the development of therapies aimed at the lipid dependence of many different cancer types. Moreover, the mechanism that we have elucidated provides a direct connection between dietary fat and tumor biology.
Abbreviations Employed
- ACACA
- acetyl-CoA carboxylase α
- ACLY
- ATP citrate lyase
- ACSS2
- acyl-CoA synthase short chain family member 2
- BC
- breast cancer
- CD36
- fatty acid translocase
- CLL
- chronic lymphocytic leukemia
- DGAT1
- diacylglycerol acyltransferase-1
- FA
- fatty acid
- FASN
- fatty acid synthase
- FFA
- free fatty acid
- GPIHBP1
- glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1
- HMGCR
- 3-hydroxy-3-methylglutaryl-CoA reductase
- HSPG
- heparan sulfate proteoglycan
- LD
- lipid droplet
- LMF1
- lipase maturation factor 1
- LPL
- lipoprotein lipase
- LPDS
- lipoprotein-depleted serum
- PLIN2
- perilipin 2
- SCD
- stearoyl-CoA desaturase
- SFM
- serum-free media
- TG
- triglyceride
- VLDL
- very low-density lipoprotein
- VLDLR
- very low-density lipoprotein receptor