Abstract C046: Aryl hydrocarbon receptor activity may lead to the downstream transcription of several genes relevant to prostate cancer progression, apoptosis and lipid metabolism

Abstract

Abstract The aryl hydrocarbon receptor (AhR) is a nuclear transcription factor and xenobiotic sensor reported to mediate diet-induced obesity and is both upregulated and constitutively active in high-grade prostate cancer. AhR activity has also been reported to contribute to proliferation and potentially disease progression in C4-2 cells (Powell et al. 2015). To determine if the aryl hydrocarbon receptor mediates transcription of genes pertinent to cancer progression, we performed an RNA-seq analysis in C4-2 AhR knockdown cells and the vehicle control. When a fold-change cutoff of ±1.5 and an adjusted p-value (p-adj) <0.05 were used, data analyses revealed several differentially expressed genes (DEGS), i.e. LEPROT, CHAC1/2, GDF11/15, CDKN2, FAS, FASTKD, ATF1/3, CCNL2, and CCNG2 with known functions involving the cell cycle, apoptosis, epigenetic modifications, tumor aggressiveness, and interestingly – lipid metabolism. Recent evidence demonstrates significant changes in the expression profile of many of these genes in response to treatment with chemotherapeutics, specifically bromocriptine (Wu et al 2023). In murine models AhR has been shown to promote diet-induced obesity coupled with metabolic dysregulation leading to obesity, which has been reported to cause malignant behaviors in prostate cancer. Leptin, a pleiotropic obesity-associated adipokine, is significantly overexpressed in mCRPC tissues. Our lab previously reported an integrative bioinformatics analysis using TCGA data (n=498) to explore the role of AHR and leptin receptor (LEPR) in prostate cancer, which revealed AHR and LEPR mRNA expression positively correlate in a subset of prostate cancer patients (P<0.05, Pearson: 0.68, R^2=0.46). We also confirmed AhR inhibits bortezomib and docetaxel -mediated apoptosis of C4-2 cells (data not shown). Further understanding of the potential interactions between metabolism and drug treatment should lead to a better understanding of the complex network of factors influencing prostate cancer progression and lead to more effective therapeutics for patients. Citation Format: Kofi K. Khamit-Kush, Joann B. Powell, Jeffrey A. Handy, Nathan J. Bowen, Daqing Wu, Valerie Odero-Marah. Aryl hydrocarbon receptor activity may lead to the downstream transcription of several genes relevant to prostate cancer progression, apoptosis and lipid metabolism [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr C046.