Anticancer Activity of the Cholesterol Exporter ABCA1 Gene

SummaryThe ABCA1 protein mediates the transfer of cellular cholesterol across the plasma membrane to apolipoprotein A-I. Loss-of-function mutations in the ABCA1 gene induce Tangier disease and familial hypoalphalipoproteinemia, both cardiovascular conditions characterized by abnormally low levels of serum cholesterol, increased cholesterol in macrophages, and subsequent formation of vascular plaque. Increased intracellular cholesterol levels are also frequently found in cancer cells. Here, we demonstrate anticancer activity of ABCA1 efflux function, which is compromised following inhibition of ABCA1 gene expression by oncogenic mutations or cancer-specific ABCA1 loss-of-function mutations. In concert with elevated cholesterol synthesis found in cancer cells, ABCA1 deficiency allows for increased mitochondrial cholesterol, inhibits release of mitochondrial cell death-promoting molecules, and thus facilitates cancer cell survival, suggesting that elevated mitochondrial cholesterol is essential to the cancer phenotype.

Graphical AbstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Cholesterol export deficiency plays a role in both cardiovascular disease and cancer ► Human colon cancer mutations in ABCA1 disable cholesterol-export function ► Excess cholesterol in mitochondria arrests suicide mechanism in cancer cells ► High membrane cholesterol in mitochondria blocks release of cell-death promoters