LIPA-driven hydrolysis of cholesteryl arachidonate promotes cancer metastasis via NF-κB

Abstract

Cholesteryl ester (CE) is an established marker in many types of aggressive cancers. Yet, the function of CE homeostasis during cancer progression is largely unknown. Here, enabled by Raman spectromicroscopy, pan-cancer bioinformatic analysis, and biocompatible Raman probe of cholesterol, LIPA was identified as the key regulator of CE hydrolysis in cancer cells. LIPA inhibition induced aberrant accumulation of CE-rich lipid droplet at single cell level. LIPA-driven CE hydrolysis was directly visualized by stimulated Raman scattering imaging of alkyne-tagged cholesterol. Cholesteryl arachidonate was identified as a dominant substrate that is rapidly hydrolyzed by LIPA. Inhibition of LIPA effectively suppressed cancer metastasis both in vitro and in vivo. Mechanistically, LIPA inhibition suppresses NF-κB signaling, while the NF-κB members positively regulate the expression level of LIPA, indicating regulation of CE homeostasis by a LIPA-CE-NFκB feedback loop. Collectively, our findings reveal that LIPA drives CE hydrolysis during cancer progression and is an important metabolic target for cancer therapy.