Cholesteryl ester accumulates in PTEN-null prostate cancer cells and supports growth and invasion.
Major finding: Cholesteryl ester accumulates in PTEN-null prostate cancer cells and supports growth and invasion.
Approach: Lipid composition was quantitatively analyzed at the single-cell level in intact prostate tissues.
Impact: Altered cholesterol metabolism may be a diagnostic feature and therapeutic target in prostate cancer.
Accumulation of lipids within enlarged intracellular lipid droplets (LD) has been observed in several cancer types. However, the role of LD formation in cancer cell biology remains poorly understood, partly because so little is known about LD composition. Yue and colleagues evaluated a spectrum of prostate pathologies and observed enlarged LDs in high-grade or metastatic prostate cancer samples, but not in normal prostate, benign prostatic hyperplasia, or prostatic intraepithelial neoplasia tissues. Examination of LDs using Raman spectromicroscopy, a recently developed approach that allows quantitative analysis of LD lipid composition at the single-cell level in intact tissues, revealed specific enrichment of cholesteryl ether (CE) within LD in all stages of prostate cancer tissue. CE accumulation was not associated with increased androgen signaling but was increased in a prostate cancer cell line lacking the tumor suppressor PTEN, suggesting that PTEN loss drives CE accumulation. Indeed, PTEN reintroduction or inhibition of downstream PI3K–AKT–mTOR signaling significantly reduced CE accumulation in prostate cancer cells. Hyperactive PI3K–AKT–mTOR signaling caused by PTEN loss led to activation of the sterol regulatory element-binding protein (SREBP) transcription factors, which sustain cholesterol biogenesis, and the low-density lipoprotein (LDL) receptor, which increased cellular uptake of the exogenous LDLs that are subsequently hydrolyzed into free cholesterol and converted into CE within lysosomes by acyl coenzyme A: cholesterol acetylase-1 (ACAT-1). Strikingly, pharmacologic inhibition of ACAT-1 with the clinically available inhibitor avasimibe not only prevented LDL uptake and increased levels of free non-esterified cholesterol, but impaired PTEN-null prostate cancer cell viability, migration, and invasion in vitro. Moreover, ACAT-1 inhibition also suppressed growth of PTEN-null prostate cancer xenografts in mice without causing toxicity. Collectively, these data demonstrate a role for CE accumulation in prostate cancer progression and suggest that CE may represent a potential therapeutic target.
Yue S, Li J, Lee SY, Lee HJ, Shao T, Song B, et al. Cholesteryl ester accumulation induced by PTEN loss and PI3K/AKT activation underlies human prostate cancer aggressiveness. Cell Metab 2014;19:393–406.
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