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

Publication ,  Journal Article
Frigo, DE; Howe, MK; Wittmann, BM; Brunner, AM; Cushman, I; Wang, Q; Brown, M; Means, AR; McDonnell, DP
Published in: Cancer Res
January 15, 2011

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.

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Published In

Cancer Res

DOI

EISSN

1538-7445

Publication Date

January 15, 2011

Volume

71

Issue

2

Start / End Page

528 / 537

Location

United States

Related Subject Headings

  • Up-Regulation
  • Signal Transduction
  • Receptors, Androgen
  • RNA, Messenger
  • Protein Kinases
  • Protein Isoforms
  • Prostatic Neoplasms
  • Oncology & Carcinogenesis
  • Male
  • Isoenzymes
 

Citation

APA
Chicago
ICMJE
MLA
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Frigo, D. E., Howe, M. K., Wittmann, B. M., Brunner, A. M., Cushman, I., Wang, Q., … McDonnell, D. P. (2011). CaM kinase kinase beta-mediated activation of the growth regulatory kinase AMPK is required for androgen-dependent migration of prostate cancer cells. Cancer Res, 71(2), 528–537. https://doi.org/10.1158/0008-5472.CAN-10-2581
Frigo, Daniel E., Matthew K. Howe, Bryan M. Wittmann, Abigail M. Brunner, Ian Cushman, Qianben Wang, Myles Brown, Anthony R. Means, and Donald P. McDonnell. “CaM kinase kinase beta-mediated activation of the growth regulatory kinase AMPK is required for androgen-dependent migration of prostate cancer cells.Cancer Res 71, no. 2 (January 15, 2011): 528–37. https://doi.org/10.1158/0008-5472.CAN-10-2581.
Frigo DE, Howe MK, Wittmann BM, Brunner AM, Cushman I, Wang Q, et al. CaM kinase kinase beta-mediated activation of the growth regulatory kinase AMPK is required for androgen-dependent migration of prostate cancer cells. Cancer Res. 2011 Jan 15;71(2):528–37.
Frigo, Daniel E., et al. “CaM kinase kinase beta-mediated activation of the growth regulatory kinase AMPK is required for androgen-dependent migration of prostate cancer cells.Cancer Res, vol. 71, no. 2, Jan. 2011, pp. 528–37. Pubmed, doi:10.1158/0008-5472.CAN-10-2581.
Frigo DE, Howe MK, Wittmann BM, Brunner AM, Cushman I, Wang Q, Brown M, Means AR, McDonnell DP. CaM kinase kinase beta-mediated activation of the growth regulatory kinase AMPK is required for androgen-dependent migration of prostate cancer cells. Cancer Res. 2011 Jan 15;71(2):528–537.

Published In

Cancer Res

DOI

EISSN

1538-7445

Publication Date

January 15, 2011

Volume

71

Issue

2

Start / End Page

528 / 537

Location

United States

Related Subject Headings

  • Up-Regulation
  • Signal Transduction
  • Receptors, Androgen
  • RNA, Messenger
  • Protein Kinases
  • Protein Isoforms
  • Prostatic Neoplasms
  • Oncology & Carcinogenesis
  • Male
  • Isoenzymes