: New targets are required for treating
prostate cancer, particularly castrate-resistant disease. Previous studies reported that
calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) expression is increased in human
prostate cancer. Here, we show that Camkk2 deletion or pharmacologic inhibition protects against
prostate cancer development in a preclinical mouse model that lacks expression of prostate-specific Pten. In contrast, deletion of
AMP-activated protein kinase (Ampk) β1 resulted in earlier onset of
adenocarcinoma development. These findings suggest for the first time that Camkk2 and Ampk have opposing effects in
prostate cancer progression. Loss of CAMKK2 in vivo or in human
prostate cancer cells reduced the expression of two key lipogenic
enzymes,
acetyl-CoA carboxylase and
fatty acid synthase. This reduction was mediated via a posttranscriptional mechanism, potentially involving a decrease in protein translation. Moreover, either deletion of CAMKK2 or activation of AMPK reduced cell growth in human
prostate cancer cells by inhibiting de novo lipogenesis. Activation of AMPK in a panel of human
prostate cancer cells inhibited cell proliferation, migration, and invasion as well as
androgen-receptor signaling. These findings demonstrate that CAMKK2 and AMPK have opposing effects on lipogenesis, providing a potential mechanism for their contrasting effects on
prostate cancer progression in vivo. They also suggest that inhibition of CAMKK2 combined with activation of AMPK would offer an efficacious therapeutic strategy in treatment of
prostate cancer. SIGNIFICANCE: These findings show that CAMKK2 and its downstream target AMPK have opposing effects on
prostate cancer development and raise the possibility of a new combined therapeutic approach that inhibits CAMKK2 and activates AMPK.