Fig. 6

A schematic model showing CRABP-II regulating PDAC cholesterol metabolism and drug resistance. By interacting with HuR, CRABP-II stabilizes the mRNA of SREBP-1c and increases expression of this center lipid metabolic transcription factor. Elevated SREBP-1c activates a cluster of cholesterol metabolic genes such as HMGCR and LDLR, resulting in increased intracellular cholesterol biosynthesis and uptake. SREBP-1c also inhibits the major cholesterol efflux transporter ABCA1 by enhancing miR-33 expression and reduces the intracellular cholesterol removal. Both arms of this machinery lead to the cholesterol accumulation in cell membrane, especially in lipid rafts, thus promoting AKT survival signaling and cancer drug resistance. The protein eraser SNIPER-11 selectively induces CRABP-II degradation in PDAC, hence interrupts CRABP-II/SREBP-1c/raft-cholesterol/AKT axis and overcomes PDAC drug resistance