Abstract
The androgen receptor (AR) is activated in prostate cancer patients undergoing androgen ablative therapy and mediates growth of androgen-insensitive prostate cancer cells, suggesting it is activated by nonandrogenic factors. We demonstrate that activated alpha subunit of heterotrimeric guanine nucleotide-binding G(s) protein activates the AR in prostate cancer cells and also synergizes with low concentration of androgen to more fully activate the AR. The G alpha(s) activates protein kinase A, which is required for the nuclear partition and activation of AR. These data suggest a role for G alpha(s) and PKA in the transactivation of AR in prostate cancer cells under the environment of reduced androgen levels.
Highlights
Prostate cancer, the most common noncutaneous malignant transformation in American men [1], starts as an androgen-dependent lesion in the prostate gland that can be successfully treated with surgical removal of the tumor or local radiation [2]
Expression of Activated G␣ Proteins Activates the androgen receptor (AR)—Activation of endogenous G protein-coupled receptors (GPCRs) induces mitogenic signaling and growth of prostate cancer cells, and inhibition of G protein signaling attenuates the growth of prostate tumors in xenograft animal models [11]
We examined the effects of G proteins on AR activation using androgen receptor response element (ARE)-regulated luciferase reporters and constitutively activated G␣ subunits (G␣q Q209L, G␣z Q205L, G␣i-1 Q204L, G␣12 Q231L, G␣13 Q226L, or G␣s Q227L) in LNCaP cells that endogenously express the AR
Summary
The G␣s activates protein kinase A, which is required for the nuclear partition and activation of AR These data suggest a role for G␣s and PKA in the transactivation of AR in prostate cancer cells under the environment of reduced androgen levels. Transition of the prostate cancer to the AI stage is associated with increased expression of plasma membrane-localized G protein-coupled receptors (GPCRs) [11], which mediate cellular responses to a diverse array of extracellular molecules, including lipid and peptide growth factors [12]. Prostate tumors express elevated levels of GPCRs as well as their ligands, suggesting these receptors are “on” and, may contribute to progression of the disease. Our data demonstrate that AR can be fully activated in the presence of castrate levels of androgen if G␣s is activated These results predict failure of hormonal therapies in cancer patients in which the Gs signaling axis is activated
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