AMP-activated protein kinase (AMPK) as a potential therapeutic target independent of PI3K/Akt signaling in prostate cancer

Choudhury, Y., Yang, Z., Ahmad, I. , Nixon, C., Salt, I. P. and Leung, H. Y. (2014) AMP-activated protein kinase (AMPK) as a potential therapeutic target independent of PI3K/Akt signaling in prostate cancer. Oncoscience, 1(6), pp. 446-456. (doi: 10.18632/oncoscience.49) (PMID:25594043) (PMCID:PMC4284621)

Abstract

Depletion of cellular energy activates the AMP-activated protein kinase (AMPK) to favor energy-producing catabolic processes during tumorigenesis. Using a panel of in vitro cell lines and resected tumors, we investigated the therapeutic value of manipulating AMPK in prostate cancer (PC). Phospho-AMPK expression was significantly elevated in human PC cells and clinical PC samples. In clinical PC, we observed a trend for increasing phospho-AMPK with increasing Gleason sum score; Phospho-AMPK expression was associated with phospho-ACC (p=0.0023). Using the paired PC3 and PC3M cells to model progressive androgen-independent PC, treatment with either 5-aminoimidazole-4-carboxamide riboside (AICAR) or A-769662 suppressed proliferation, migration and invasion in both cell lines, and down-regulated mTOR and P70S6Ki levels regardless of the Akt status. Involvement of AMPK was confirmed by Compound C (AMPK inhibitor) and siRNA-mediated AMPK silencing. Despite similar functional responses in PC3 and PC3M cells, AMPK activation resulted in sustained phospho-Akt activation in PC3M cells, but not in PC3 cells. This prompted the addition of the PI3K inhibitor LY-294002 to AICAR treatment of PC3M cells in a proliferation assay. Interestingly, we found no synergistic effects upon combined treatment. Collectively, these findings support AMPK as a potential therapeutic target independent of PI3K/Akt signalling.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Ahmad, Professor Imran and Nixon, Mr Colin and Salt, Dr Ian and Leung, Professor Hing
• Authors: Choudhury, Y., Yang, Z., Ahmad, I., Nixon, C., Salt, I. P., and Leung, H. Y.
• Subjects: Q Science > QH Natural history > QH345 Biochemistry; R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences; College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health; College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
• Journal Name: Oncoscience
• Publisher: Impact Journals, LLC.
• ISSN: 2331-4737
• ISSN (Online): 2331-4737
• Copyright Holders: Copyright © 2014 Impact Journals, LLC.
• First Published: First published in Oncoscience 1(6):446-456
• Publisher Policy: Reproduced under a Creative Commons License