Accelerated
cholesterol and lipid metabolism are the hallmarks of
cancer and contribute to malignant transformation due to the obligatory requirement for
cholesterol for the function of eukaryotic membranes. To build new membranes and maintain active signaling,
cancer cells depend on high intensity of endogenous
cholesterol biosynthesis and uptake of
lipid particles. This metabolic dependency of
cancer cells on
cholesterol and other
lipids is tightly regulated by the
cholesterol homeostasis network, including (i)
sterol response element-
binding proteins (SREBP), master transcriptional regulators of
cholesterol and
fatty acid pathway genes; (ii) nuclear
sterol receptors (
liver X receptors, LXR), which coordinate growth with the availability of
cholesterol; and (iii)
lipid particle receptors, such as low-density
lipid particle (
LDL) receptor, providing exogenous
sterol and
lipids to
cancer cells. In addition, activity of oncogenic receptors, such as MUC1 or EGFR, accelerates
sterol uptake and biosynthesis. Therefore, a general strategy of reducing the
cholesterol pool in
cancer cells is challenged by the highly efficient feedback loops compensating for a blockade at a single point in the
cholesterol homeostatic network. Besides the well-established structural role of
cholesterol in membranes, recent studies have uncovered potent
biologic activities of certain
cholesterol metabolic precursors and its oxidized derivatives,
oxysterols. The former, meiosis-activating
sterols, exert effects on trafficking and signaling of oncogenic
EGF receptor (EGFR).
Cholesterol epoxides, the highly active products of
cholesterol oxidation, are being neutralized by the distal
sterol pathway
enzymes, emopamyl-
binding protein (EBP) and dehydrocholesterol-7
reductase (DHCR7). These recently discovered "moonlighting" activities of the
cholesterol pathway genes and metabolites expand our understanding of the uniquely conserved roles these
sterol molecules play in the regulation of cellular proliferation and in
cancer.