CaM Kinase Kinase β-Mediated Activation of the Growth Regulatory Kinase AMPK Is Required for Androgen-Dependent Migration of Prostate Cancer Cells

Abstract

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 Ca 2þ /calmodulin-dependent protein kinase kinase b (CaMKKb) 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 CaMKKb splice variant and (b) increase functional CaMKKb protein levels as determined by the phosphorylation of both CaMKI and AMP-activated protein kinase (AMPK), two of CaMKKb's primary substrates. Importantly, inhibition of the CaMKKb-AMPK, but not CaMKI, signaling axis in prostate cancer cells by pharmacological inhibitors or siRNA-mediated knockdown blocks androgenmediated migration and invasion. Conversely, overexpression of CaMKKb alone leads to both increased AMPK phosphorylation and cell migration. Given the key roles of CaMKKb and AMPK in the biology of prostate cancer cells, we propose that these enzymes are potential therapeutic targets in prostate cancer. Cancer Res; 71(2); 528-37.Ó2010 AACR.

MicroRNA-224 and its target CAMKK2 synergistically influence tumor progression and patient prognosis in prostate cancer

“…Growing evidence has indicated that CaMKK2 may be in a feedback circuit to maintain androgen receptor (AR) activity, which regulates prostate growth and is the principal target of therapy aimed at preventing growth and spreading of androgen-dependent PCa [22]. Frigo et al [23] showed that androgens could stimulate the expression of CAMKK2 in androgen-dependent PCa cells, and identified CAMKK2 and AMPK as components of the signaling pathway downstream of the AR that mediates PCa cell migration and invasion. However, our data showed that CAMKK2 did not have the significant affect on cell invasion and migration of DU145 cells.…”

Calcium/Calmodulin-dependent Protein Kinase Kinase 2: Roles in Signaling and Pathophysiology

“…In an attempt to determine androgen-responsive genes, two groups recently identified CaMKK2 to be associated with prostate cancer (79,80). Frigo et al (80) revealed that androgens stimulate the expression of CaMKK2 in androgen-dependent prostate cancer cells.…”

“…2). Generation and/or splicing of the primary transcript is a regulated event, and in prostate cancer cells, transcription can be regulated by androgens (16,17,79,80). CaMKK2 protein is also subject to numerous post-translational modifications ( Fig.…”

CtBP2 Modulates the Androgen Receptor to Promote Prostate Cancer Progression

“…Conversely, we observed inhibition of highly androgen-responsive gene inductions following CTBP2 knockdown, thereby suggesting the positive effect of CtBP2 on these androgen signals. Positively androgen-regulated genes include CAMKK2 (22,23), APP (12), and IGF1R (24), which are associated with prostate cancer progression. Thus, we assume that CtBP2 promotes tumor growth by activating such genes.…”