Continued reliance on
androgen receptor (AR) signaling is a hallmark of
prostate cancer, including the development of
castration-resistant
prostate cancer (CRPC), making it an attractive therapeutic target for
prostate cancer treatment.
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 possesses the ability to inhibit
ligand-dependent and -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, in a panel of
androgen-responsive and -independent
prostate cancer cells. The decrease in AR levels induced by
mahanine occurs posttranslationally by proteasomal degradation, without any change in the AR gene expression.
Mahanine treatment induces an outward movement of the AR from the nucleus to the cytoplasm, leading to an initial increase 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. Collectively, our data demonstrate that
mahanine strongly disrupts AR signaling and inhibits the growth of
androgen-dependent and -independent
prostate cancer cells, thereby implicating a therapeutic role of
mahanine in
prostate cancer treatment.