Lysosomal acid lipase-driven cholesterol ester hydrolysis promotes cancer aggressiveness
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Abstract
Aberrant cholesterol ester (CE) accumulation in various cancer is well documented, while abrogation of cholesterol esterification can effectively suppress cancer aggressiveness. However, the exact role of CE in cancer progression remains elusive. To understand the function of CE in cancer development, we sought to identify the key regulator and functional products of CE hydrolysis and elucidate its specific function and mechanisms in cancer. Here, we found that Lysosomal Acid Lipase (LIPA) was upregulated and correlated with unfavorable prognosis in many cancers by bioinformatics analysis. Combining with experiment results, we found that CE hydrolysis is mediated by LIPA in cancer cells. The inhibition of LIPA significantly increased lipid accumulation into lipid droplets (LDs), which contain a high level of CE and the most variable CE was cholesteryl arachidonate. Besides, both genetic and pharmacologic suppression of LIPA impaired cell migration, instead of proliferation. According to the prediction bioinformatics analysis using TCGA dataset, epithelial-mesenchymal transition (EMT), PI3K-AKT, and NF-kB signaling pathways might be involved in LIPA-driven cancer progression. Finally, we further validated that knockdown of LIPA impaired the expression levels of EMT markers. Collectively, LIPA-driven CE hydrolysis is an important metabolic process in cancer progression by contributing to cancer aggressiveness.