AMP-activated protein kinase (AMPK) as a potential therapeutic target independent of PI3K/Akt signaling in prostate cancer
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https://doi.org/10.18632/oncoscience.49
Yashmin Choudhury1,2,3, Zichu Yang4, Imran Ahmad1,2, Colin Nixon2, Ian P. Salt4 and Hing Y. Leung1,2
1 Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
2 Beatson Institute for Cancer Research, Glasgow, UK
3 Current address - Department of Biotechnology, Assam University, Silchar, India
4 Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK
Correspondence:
Hing Y. Leung , email:
Keywords: Prostate cancer, AMP-activated protein kinase (AMPK), PI3K, 5-aminoimidazole-4-carboxamide riboside (AICAR), A-769662
Received: May 12, 2014 Accepted: June 02, 2014 Published: June 04, 2014
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.
