Metabolic reprogramming allows cancer cells to sustain high proliferative rates and resist cell death. Whereas alterations to glucose and amino acid metabolism have been extensively studied, altered lipid metabolism in cancer is increasingly recognized based on the findings of imbalanced lipid signaling network and dysregulated lipogenic enzymes. Storage of neutral lipids in lipid droplets (LDs), an essential aspect of lipid metabolism, is however long underappreciated until recent advances in LD biology. In human prostate cancer cell lines, neutral lipid accumulation was commonly seen and partially attributed to the up-regulation of fatty acid synthase, a key lipogenic enzyme catalyzing fatty acid biosynthesis and implicated in many human malignancies including prostate cancer. However, because the composition of LDs is not accessible with fluorescence microscopy, the exact role of lipid accumulation in prostate cancer progression remains elusive. By vibration-based spectroscopic imaging of 65 specimens collected from 61 prostate cancer patients and healthy donors, we found for the first time a marked shift from lipofuscin-like autofluorescent granules in normal, benign, and prostatic intraepithelial neoplasia lesions to cholesteryl ester (CE)-rich LDs in high-grade and metastatic prostate cancers. Quantitatively, CE amount was found ∼5 folds higher in high-grade relative to low-grade prostate cancers. Cellular studies demonstrate that the activated PI3K/Akt/mTOR/SREBP pathway accounts for accumulation of CEs via elevated LDL uptake and cholesterol esterification. Blockage of cholesterol esterification with an acetyl-coA cholesterol acyltransferase (ACAT) inhibitor significantly slows the growth and induces apoptosis of prostate cancer both in vitro and in vivo. These findings suggest that CE can be a quantifiable molecular marker for diagnosis of prostate cancer, especially for differentiation between low-grade and high-grade prostate cancers which currently has up to 40% inter-observer discordance. Moreover, targeting the altered cholesterol metabolism opens new opportunities for treating advanced prostate cancer in human patients.
Citation Format: Shuhua Yue, Junjie Li, Seung Young Lee, Tian Shao, Bing Song, Liang Cheng, Chang-Deng Hu, Xiaoqi Liu, Timothy L. Ratliff, Ji-Xin Cheng. Spectroscopic imaging unveils altered cholesterol metabolism in prostate cancer . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1893. doi:10.1158/1538-7445.AM2013-1893
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.