Abstract 3336: Regulation of liver X receptor protein stability by novel ligands in pancreatic cancer cells

Abstract

Abstract Liver X Receptors (LXRs) are nuclear receptors that act as ligand-modulated transcription factors. LXRs are overexpressed in various cancers, including pancreatic cancer, and targeting LXR with small molecule ligands has emerged as a promising therapeutic strategy in cancer. Current small molecule LXR ligands were originally developed for the treatment of atherosclerosis and other metabolic diseases. To identify ligands specifically targeting cancer cells, we screened a focused library of drug-like molecules predicted to bind to LXR using molecular docking. In the screen, novel LXR ligand GAC0001E5 (1E5) exhibited significant anti-proliferative effects in human pancreatic ductal adenocarcinoma (PDAC) cell lines. Functionally, 1E5 is an LXR inverse agonist which decreases LXR target gene expression and a “degrader” of LXR proteins following prolonged treatment. We posit that this novel ligand inhibits PDAC cells by downregulating the expression of LXR target genes. To test this hypothesis, we treated cancer cells with the previously described LXR inverse agonist SR9238 and examined its effect on cancer cell proliferation. Interestingly, treatments with SR9238 had no effect on pancreatic cancer cell proliferation as compared to the novel ligand 1E5 and the 1E5 derivative KD-95, suggesting that LXR inverse agonism was insufficient to inhibit cell proliferation. To determine whether SR9238 has similar effects on LXR protein levels as novel ligands, we performed western analysis of protein expression following ligand treatment. In contrast to the novel ligands 1E5 and KD-95, treatments with SR9238 increased LXR protein levels. Furthermore, time-course studies in cycloheximide treated cells indicated that novel ligands decreased protein stability whereas SR9238 had the opposite effect. Inhibition of proteasomal degradation and autophagy abolished the effects of 1E5 and KD-95 in a cell line-dependent manner. Related to these observations, previously published data revealed that knockdown of LXR expression greatly diminished PDAC cell proliferation. Taken together, these findings indicate that LXR expression is essential in pancreatic cancer cells and suggest that the novel ligands may disrupt its involvement in protein-protein interactions and non-genomic mechanisms. Citation Format: Abhinav Bagchi, Kasuni T. Gamage, Scott R. Gilbertson, Chin-Yo Lin. Regulation of liver X receptor protein stability by novel ligands in pancreatic cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3336.