Phosphorylation of HSP90 by protein kinase A is essential for the nuclear translocation of androgen receptor

Prostate cancer is one of the major health problems globally. It causes 1 in 6 deaths in males worldwide (Jemal et al., 2005). Androgens play a major role in the normal growth and development of prostate glands and in the progression of prostate cancer (Ruizeveld de Winter JA et al., 1994). Initially, prostate cancer depends on androgen for proliferation which can be treated by surgical removal of tumors (Anscher and M.S., 2004). The hormonal therapies lead to temporary shrinkage of the tumor but cancer reappears in the form of Androgen independent (AI) prostate cancer. In AI prostate cancer, AR gets activated even in the presence of low levels of androgens (Feldman et al., 2001). Androgen‐insensitive cancer cells express AR and require a functioning AR to grow (Zegarra‐Moro et al., 2002). Hence, identification of the means by which cancer cells activate the AR, especially in the presence of low concentrations of androgen, is critical for improving the outcome of late‐stage disease. Previous studies show that PKA can synergize with low levels of androgen to enhance androgen signaling leading to castration‐resistant prostate cancer. Identification of the mechanism by which PKA activates AR could lead to the development of therapeutic targets for prostate cancer. Our results demonstrate that PKA plays a very important role in the translocation of AR into the nucleus. In the absence of Androgen, AR is in complex with Hsp90 molecular chaperones. Upon Androgen binding, AR dissociates from Hs90 and binds to Hsp27 which helps in its translocation. PKA phosphorylates Hsp90 at Thr89 which leads to the release of AR from Hsp90 and its translocation into the nucleus. This information can be used for developing small molecular inhibitors against Hsp90 to target prostate cancer patients.