Abstract 2629: Constitutive AhR signaling enhances androgen receptor signaling and growth in prostate cancer cells

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The aryl hydrocarbon receptor (AhR) has been reported to interact with multiple signaling pathways during prostate cancer progression to castration resistant prostate cancer (CRPC) including the androgen receptor. Previously published data from our lab shows that AhR protein is overexpressed and constitutively active in castration resistant (DU145, PC3 and PC3M) prostate cancer cells. Pharmacological inhibition of AhR in these advanced prostate cancer cell lines reduced the growth rate under androgen depleted conditions. Furthermore, shRNA mediated depletion of AhR expression in castration resistant C4-2 cells, which were derived from hormone sensitive LNCaP cells, resulted in decreased expression of androgen responsive genes as well as a decreased growth rate which was comparable to LNCaP cell growth. In the present study, we evaluate cloneA (moderate increase in AhR) and CloneB (high increase in AhR) for alterations in AhR and AR signaling. AhR was overexpressed in LNCaP using PLNCX2 retrovirus vector containing AhR cDNA to determine if ectopic overexpression alone induces a castrate resistant phenotype. The highly overexpressed AhR clone (CloneB) illustrated further increase in transcriptional and promotor activity for AhR and AR compared to the moderately overexpressed AhR clone (Clone A) and control. Western blot analysis showed more AhR, AR, cSrc, and pSrc protein expression in clones compared to empty vector control. AhR overexpression was found to induce several biological properties such as migration, invasion, proliferation, and promotion of G1 to S phase during the cell cycle. Bicalutamide treatment had no effect on AR transcriptional activity in either clone, proving resistance to anti-androgen therapy. Our results confirm that overexpression of AhR induces constitutive AhR activity and stimulates androgen receptor signaling. This suggests a role for AhR in the development of CRPC. Citation Format: Maryam Ghotbaddini, Sakura McLaughlin, Kailen Turner, Devyn Pirtle, Joann B. Powell. Constitutive AhR signaling enhances androgen receptor signaling and growth in prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2629.