Endocytosis of very low-density lipoproteins: an unexpected mechanism for lipid acquisition by breast cancer cells[S]

Leslie E. Lupien; Katarzyna Bloch; Jonas Dehairs; Nicole A. Traphagen; William W. Feng; Wilson L. Davis; Thea Dennis; Johannes V. Swinnen; Wendy A. Wells; Nicole C. Smits; Nancy B. Kuemmerle; Todd W. Miller; William B. Kinlaw

Endocytosis of very low-density lipoproteins: an unexpected mechanism for lipid acquisition by breast cancer cells[S]

2020

We previously described the expression of CD36 and LPL by breast cancer (BC) cells and tissues and the growth-promoting effect of VLDL observed only in the presence of LPL. We now report a model in which LPL is bound to a heparan sulfate proteoglycan motif on the BC cell surface and acts in concert with the VLDL receptor to internalize VLDLs via receptor-mediated endocytosis. We also demonstrate that gene-expression programs for lipid synthesis versus uptake respond robustly to triglyceride-rich lipoprotein availability. The literature emphasizes de novo FA synthesis and exogenous free FA uptake using CD36 as paramount mechanisms for lipid acquisition by cancer cells. We find that the uptake of intact lipoproteins is also an important mechanism for lipid acquisition and that the relative reliance on lipid synthesis versus uptake varies among BC cell lines and in response to VLDL availability. This metabolic plasticity has important implications for the development of therapies aimed at the lipid dependence of many types of cancer, in that the inhibition of FA synthesis may elicit compensatory upregulation of lipid uptake. Moreover, the mechanism that we have elucidated provides a direct connection between dietary fat and tumor biology..

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