Inhibition of constitutive aryl hydrocarbon receptor (AhR) signaling attenuates androgen independent signaling and growth in (C4-2) prostate cancer cells

Abstract

The aryl hydrocarbon receptor is a member of the basic-helix-loop-helix family of transcription factors. AhR mediates the biochemical and toxic effects of a number of polyaromatic hydrocarbons such as 2,3,7,8,-tetrachloro-dibenzo-p-dioxin (TCDD). AhR is widely known for regulating the transcription of drug metabolizing enzymes involved in the xenobiotic metabolism of carcinogens and therapeutic agents, such as cytochrome P450-1B1 (CYP1B1). Additionally, AhR has also been reported to interact with multiple signaling pathways during prostate development. Here we investigate the effect of sustained AhR signaling on androgen receptor function in prostate cancer cells. Immunoblot analysis shows that AhR expression is increased in androgen independent (C4-2) prostate cancer cells when compared to androgen sensitive (LNCaP) cells. RT-PCR studies revealed constitutive AhR signaling in C4-2 cells without the ligand induced activation required in LNCaP cells. A reduction of AhR activity by short RNA mediated silencing in C4-2 cells reduced expression of both AhR and androgen responsive genes. The decrease in androgen responsive genes correlates to a decrease in phosphorylated androgen receptor and androgen receptor expression in the nucleus. Furthermore, the forced decrease in AhR expression resulted in a 50% decline in the growth rate of C4-2 cells. These data indicates that AhR is required to maintain hormone independent signaling and growth by the androgen receptor in C4-2 cells. Collectively, these data provide evidence of a direct role for AhR in androgen independent signaling and provides insight into the molecular mechanisms responsible for sustained androgen receptor signaling in hormone refractory prostate cancer.

The Aryl Hydrocarbon Receptor Is Constitutively Active in Advanced Prostate Cancer Cells

“…We have previously reported that AhR is required to maintain hormone independent signaling and growth by the androgen receptor in C4-2 prostate cancer cells. This evidence shows a direct role for AhR in androgen receptor dependent growth of prostate cancer cells [29]. In this present study we show that AhR is constitutively active in advanced prostate cancer cells and that ablation of constitutive AhR signaling to inhibit androgen independent growth is not dependent on androgen receptor status.…”

Role of the aryl hydrocarbon receptor in carcinogenesis and potential as an anti-cancer drug target

“…There is evidence that AhR ligands are antiandrogenic in AR-expressing prostate cancer cells, and the AhR itself is growth inhibitory (Gluschnaider et al 2010). In contrast, knockdown of the AhR in AR-negative prostate cancer cells decreases proliferation (Tran et al 2013), multiple AhR ligands induce pro-invasion MMP9 (Haque et al 2005), and the AhR antagonist CH223191 inhibits growth (Richmond et al 2014). In TRAMP mice which are AR-positive, the evidence suggests that the AhR and its ligands are tumor growth inhibitory, although some mixed results were observed for TCDD (Fritz et al 2007; Fritz et al 2009; Moore et al 2016).…”

A TDO2-AhR Signaling Axis Facilitates Anoikis Resistance and Metastasis in Triple-Negative Breast Cancer

“…However, AhR nuclear localization and transcriptional activity is clearly increased in TNBC in suspension culture, and other recent studies find that AhR affects growth and migration of breast cancer cells [27, 28] and castrate-resistant prostate cancer cells [46]. Studies examining AhR expression in breast cancer primary tumors found that higher AhR expression correlates with good prognosis [47].…”