Antitumoral alkylphospholipids induce cholesterol efflux from the plasma membrane in HepG2 cells.

Alkylphospholipid (APL) analogs are promising candidates in the search for treatments of cancer. Previous studies conducted in our laboratory indicate that, after prolonged treatment, they alter cholesterol homeostasis in HepG2 cells. Here we describe the effects that different APLs exert upon this cell line after a 1-h exposure in a serum-free medium, including 1) a rapid, significant increase in cholesterol efflux into the extracellular medium, which consequently provoked a depletion of cholesterol in the plasma membrane (further assays conducted in an attempt to return to control cholesterol levels were only partially successful); 2) use of methyl-β-cyclodextrin, which indicated that APLs acted in a way similar to this agent that is used frequently to modulate membrane cholesterol levels; 3) the phosphorylation of Akt that showed that this critical regulator for cell survival was modulated by changes in cholesterol levels induced in the plasma membrane by APLs; and 4) membrane cholesterol depletion that is not related to the impairment of cholesterol traffic produced by APLs. Thus, we have found that antitumoral APLs efficiently deplete membrane cholesterol, which may be one important factor in determining the early biological actions of APLs.