Regulation of Prostate Cancer Metabolism and Invasiveness by the Liver X Receptor
Prostate cancer (PCa) progression is marked by characteristic changes in PCa cell metabolism. During early PCa cell transformation, activation of the oncogene, c-MYC, fosters a metabolic switch from glycolytic to oxidative metabolism and increases lipid synthesis. This switch in metabolic activity and increased expression of lipid synthesis genes is characteristic of castration resistant metastatic PCa. The liver X receptor (LXR) is a transcriptional regulator expressed in prostate epithelial cells that plays an important role in cholesterol, lipogenic and carbohydrate homeostasis. Recently, it has been demonstrated that loss of the bona-fide PCa tumor-suppressor, PTEN, results in oncogene driven dysregulation of LXR-target gene expression. Therefore, we theorized that LXRs may play a role in directing PCa metabolism and treatment resistance.
First, we assessed DNA and RNA sequencing data from prostate tumor samples to determine if lipid synthesis enzyme expression correlated with LXR expression in tumors. Second, we compared the expression of LXRs and LXR target genes in culture PCa cells that display differential dependence on androgens for growth. Third, we tested whether disruption of LXR transcriptional activity using pharmacological and genetic approaches could inhibit prostate tumor metabolism and block PCa metastasis.
Prostate tumor samples had more than twofold higher LXR target gene expression than normal prostate samples. Expression of LXR β positively correlated with the expression of lipid synthesis genes SREBP1c, FASN, and SCD1 (pearson r=.93, p=.03) that drive cancer cell metabolic activity. LXR expression positively correlated with androgen independent growth, resistance to chemotherapy, and increased risk of metastatic recurrence. Patients with primary tumors with relatively low LXR expression had a maximum recurrence free survival of 80 months compared to patients with high LXR expression of 15 months. LXR expression in a number of PCa cell lines also showed correlation with metastatic potential. The LXR inverse agonist SR9243, a pharmacologically active compound that suppresses LXR transcriptional activity, potently inhibited PCa tumor growth.
Results suggest LXR signaling may be hijacked by oncogenic signaling leading to upregulation of lipogenesis gene expression in prostate cancer cells that helps promote androgen independent metastatic disease.
Funding: This project was partially funded by grants from the NIH NCI (RCA205096A) and Midwest Stone Institute and Midwest Therapy