While patients with advanced
prostate cancer initially respond favorably to
androgen ablation
therapy, most experience a relapse of the disease within 1-2 years. Although
hormone-refractory disease is unresponsive to
androgen-deprivation,
androgen receptor (AR)-regulated signaling pathways remain active and are necessary for
cancer progression. Thus, both AR itself and the processes downstream of the receptor remain viable targets for therapeutic intervention. Microarray analysis of multiple clinical cohorts showed that the
serine/threonine kinase Ca2+/
calmodulin-dependent protein kinase kinase β (CaMKKβ) is both highly expressed in the prostate and further elevated in
prostate cancers. Using cellular models of
prostate cancer, we have determined that
androgens (a) directly increase the expression of a CaMKKβ splice variant and (b) increase functional CaMKKβ
protein levels as determined by the phosphorylation of both CaMKI and
AMP-activated protein kinase (AMPK), two of CaMKKβ's primary substrates. Importantly, inhibition of the CaMKKβ-AMPK, but not CaMKI, signaling axis in
prostate cancer cells by pharmacological inhibitors or
siRNA-mediated knockdown blocks
androgen-mediated migration and invasion. Conversely, overexpression of CaMKKβ alone leads to both increased AMPK phosphorylation and cell migration. Given the key roles of CaMKKβ and AMPK in the biology of
prostate cancer cells, we propose that these
enzymes are potential therapeutic targets in
prostate cancer.