Attenuation of androgen receptor-dependent transcription by the serine/threonine kinase Pim-1

Abstract

Androgens play a key role in the regulation of the normal prostate as well as in the promotion and progression of prostate cancer. Recently, an oncogenic serine/threonine kinase, Pim-1, was reported to be overexpressed in prostate cancer. To elucidate whether Pim-1 is capable of modulating androgen signaling, we studied the effects of Pim-1 on androgen receptor (AR)-dependent transcription. Under transient transfection conditions, Pim-1 attenuated transcriptional activity of AR in a dose-dependent fashion in PC-3, HeLa, and COS-1 cells, whereas a kinase-negative mutant of Pim-1, Pim-1 (K67M), showed no repressive activity. In contrast, ectopic expression of Pim-1 did not influence the activity of endogenous AR in LNCaP cells. This was, however, not a result of the T877A mutation present in AR of LNCaP cells, because that AR mutant was repressed by Pim-1 as efficiently as wild-type AR when expressed in PC-3 prostate cancer cells. Pim-1 inhibited AR mutants devoid of the ligand-binding domain or the core amino-terminal transactivation function but failed to influence the DNA binding of AR. Because we found no evidence for phosphorylation of AR by Pim-1 or for direct interaction between these proteins, Pim-1 is likely to influence AR activity via an indirect mechanism, possibly involving phosphorylation of a coregulator and/or a component of the transcription machinery. Overexpression of Pim-1 may thus attenuate androgen response during progression of prostate cancer in a cell context-dependent fashion.