Abstract 944: Down-regulation of CAMKK2 by androgen deprivation induces castration-resistant prostate cancer

Abstract

Abstract One of the mechanisms through which prostate cancer (PCa) relapses after androgen deprivation therapy (ADT) is to become androgen-hypersensitive and adapt to the low concentration of androgen during ADT. cDNA microarray analysis between PCa tissues before ADT and normal prostate tissues revealed that the level of calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) mRNA was overexpressed 6 times in PCa more than in normal prostate. Immunohistochemical analysis of CAMKK2 protein using prostate tissue microarray showed that CAMKK2 protein was expressed well in PCa compared with normal tissue. However, the expression of CAMKK2 for the high grade PCa diminished compared with the low grade PCa. Moreover, we confirmed that the narrowness of a positive regional area of the CAMKK2 expression before ADT was a poor prognostic factor. Expression of CAMKK2 mRNA was up-regulated in the presence of DHT in LNCaP cells. Stable overexpression of CAMKK2 in LNCaP cells (LNCaP/GFP-CAMKK2), however, attenuated androgen-sensitivity. Tumorigenesis of LNCaP/GFP-CAMKK2 cells by subcutaneous injection in male SCID mice was also inhibited compared with control cells irrespective of castration. In contrast, knockdown of CAMKK2 mRNA in LNCaP cells induced androgen-hypersensitivity and stimulated LNCaP cell proliferation without DHT. Overexpression and knockdown of CAMKK2 in the presence of DHT were correlated with activation and inactivation of AMP-activated protein kinase (AMPK) that is a key kinase important for regulating cell proliferation, respectively. AMPK activation inhibited LNCaP cell proliferation. Taken together, induction of androgen-hypersensitivity after ADT may be involved in down-regulation of CAMKK2. This result may provide new therapeutic approach to keep androgen-sensitivity of PCa after ADT. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 944. doi:1538-7445.AM2012-944