CaM kinase kinase β-mediated activation of the growth regulatory kinase AMPK is required for androgen-dependent migration of prostate cancer cells

Daniel E. Frigo, Matthew K. Howe, Bryan M. Wittmann, Abigail M. Brunner, Ian Cushman, Qianben Wang, Myles Brown, Anthony R. Means, Donald P. McDonnell

Research output: Contribution to journalArticlepeer-review

83 Scopus citations

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 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 androgenmediated 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.

Original languageEnglish (US)
Pages (from-to)528-537
Number of pages10
JournalCancer research
Volume71
Issue number2
DOIs
StatePublished - Jan 15 2011

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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