Cholesteryl Ester Accumulation Induced by PTEN Loss and PI3K/AKT Activation Underlies Human Prostate Cancer Aggressiveness

Altered lipid metabolism is increasingly recognized as a signature of cancer cells. Enabled by label-free Raman spectromicroscopy, we performed quantitative analysis of lipogenesis at single-cell level in human patient cancerous tissues. Our imaging data revealed an unexpected, aberrant accumulation of esterified cholesterol in lipid droplets of high-grade prostate cancer and metastases. Biochemical study showed that such cholesteryl ester accumulation was a consequence of loss of tumor suppressor PTEN and subsequent activation of PI3K/AKT pathway in prostate cancer cells. Furthermore, we found that such accumulation arose from significantly enhanced uptake of exogenous lipoproteins and required cholesterol esterification. Depletion of cholesteryl ester storage significantly reduced cancer proliferation, impaired cancer invasion capability, and suppressed tumor growth in mouse xenograft models with negligible toxicity. These findings open opportunities for diagnosing and treating prostate cancer by targeting the altered cholesterol metabolism. [Display omitted] •Aberrant cholesteryl ester accumulation is found in advanced human prostate cancer•Cholesteryl ester accumulation is induced by PTEN loss and PI3K/AKT activation•Inhibition of cholesterol esterification impairs cancer aggressiveness Altered lipid metabolism is a signature of cancer cells. Yue et al. apply label-free Raman spectromicroscopy to reveal an aberrant accumulation of esterified cholesterol, induced by PTEN loss and PI3K/AKT activation, in advanced human prostate cancer. Inhibition of cholesterol esterification impairs cancer aggressiveness.