Mahanine Disrupts Androgen Receptor Signaling in Human Prostate Cancer Cells
Continued reliance on androgen receptor (AR) signaling is an established hallmark of prostate cancer and castration-resistant prostate cancer (CRPC). Recent findings implicate the androgen receptor splice variant, ARv7 in CRPC progression, and increasing evidence suggests that targeting both, the full-length AR and its splice variant ARv7 can have beneficial therapeutic outcomes in patients with CRPC. Mahanine is a novel carbazole alkaloid derived from the leaves of Murraya koenigii, commonly known as the curry leaf plant, which grows widely across East Asia. We show here that mahanine inhibits ligand-dependent and ligand-independent AR transactivation, leading to a prominent decline in AR target gene expression. Mahanine treatment causes a time- and dose- dependent decline in AR protein levels, including truncated AR splice variants such as ARv7, in a panel of androgen-responsive and androgen-independent prostate cancer cells. The decrease in AR levels induced by mahanine occurs post-translationally by proteasomal degradation, without any change in AR gene expression. Mahanine treatment induces an outward movement of the AR from the nucleus to the cytoplasm, leading to an initial rise in cytoplasmic AR levels, followed by a gradual decline in the AR levels in both cellular compartments. Ligand-induced AR phosphorylation at Ser-81, a phospho-site associated with prostate cancer cell growth and AR transactivity, is greatly diminished in the presence of mahanine. The decline in AR phosphorylation at Ser-81 by mahanine occurs via the inactivation of mitotic kinase, CDK1. Additionally, by screening a library of structural analogues of mahanine we have identified a lead compound, Ked-6-187, with increased potency when compared to mahanine in its ability to disrupt AR signaling and prostate cancer cell growth. Furthermore, we found that the Ked-6-187 was more effective than second generation anti-androgens in inhibiting AR signaling and growth in androgen-independent prostate cancer cells. Collectively, these findings indicate that mahanine and its synthetic analogue, Ked-6-187 strongly disrupt androgen receptor signaling and inhibit the growth of androgen-dependent and -independent prostate cancer cells and demonstrate improved therapeutic potential over second generation anti-androgens which are clinically approved for CRPC treatment.
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