Targeted metabolomics revealed a key metabolic reprogramming in cholesterol biosynthesis pathway upon PTEN re-expression in PTEN-null, metastatic and castration-resistant prostate cancer

Abstract

Prostate cancer is the second most diagnosed type of cancer in males worldwide. Androgen signaling is a main driver of prostate cancers progression and androgen-deprivation therapies (ADT) are remained to be main treatment for preventing progression of the disease. Although ADT is effective at the first line and prolongs overall survival of the patients, eventually disease is recurred, develop resistance to castration and grow in an androgen-independent state, which completely eliminate ADT option. Metastatic and castration-resistant prostate cancers (mCPRC) are the most fatal type of the disease without any effective treatments currently, which is why, molecular drivers that contribute to emergence of castration-resistant phenotype need to be elucidated in order to develop efficient therapeutics against them. Metabolic reprogramming is one of the crucial hallmarks of cancer and loss-of tumor suppressor PTEN is an early and a frequent genetic alteration in prostate cancers, which leads to a hyperactivation of PI3K/Akt/mTOR axis and affects cellular metabolism widely. In this study, we aimed to unveil changes in the metabolome of C4-2 cells which are the type of mCRPC with a PTEN-null genetic background and target metabolic vulnerabilities of these cells. In order to address the question, we employed high-throughput metabolomics assay and revealed changes on metabolome of the cells upon re-expression of PTEN. We found that PTEN re-expression impaired the sphingolipid and cholesterol biosynthesis pathways of C4-2 cells. Upon PTEN re-expression, metabolism of C4-2 cells had tendency to increase the level of anti-survival metabolite; ceramide, and decrease pro-survival metabolite; sphingosine-1-phosphate. In addition to that, PTEN re-expression significantly impaired and downregulated the cholesterol metabolism of these cells. To target these metabolic vulnerabilities, we combined inhibitors of sphingolipid and cholesterol metabolisms with FDA-approved androgen antagonist, MDV3100, to determine possible synergistic effects from the combination of drugs. MDV3100 single treatment had only cytostatic effect on viability of C4-2 cells and combination of simvastatin, cholesterol metabolism inhibitor, with MDV3100 significantly decreased the cellular viability and resulted in significant synergistic effects in inhibiting the growth of C4-2 cells. Thus targeting cholesterol pathway in combination with androgen-deprivation therapies would be a promising approach to develop new combinatorial therapies and combat mCRPC.