title: AMP-activated protein kinase (AMPK) as a potential therapeutic target independent of PI3K/Akt signaling in prostate cancer.
abstract: Depletion of cellular energy activates the AMP-activated 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.
authors.affiliation: Institute of Cancer Sciences, University of Glasgow, Glasgow, UK ; Beatson Institute for Cancer Research, Glasgow, UK ; Current address - Department of Biotechnology, Assam University, Silchar, India.
authors.forename: Yashmin
authors.initials: Y
authors.lastname: Choudhury
authors.affiliation: Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
authors.forename: Zichu
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Institute of Cancer Sciences, University of Glasgow, Glasgow, UK ; Beatson Institute for Cancer Research, Glasgow, UK.
authors.forename: Imran
authors.initials: I
authors.lastname: Ahmad
authors.affiliation: Beatson Institute for Cancer Research, Glasgow, UK.
authors.forename: Colin
authors.initials: C
authors.lastname: Nixon
authors.affiliation: Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
authors.forename: Ian P
authors.initials: IP
authors.lastname: Salt
authors.affiliation: Institute of Cancer Sciences, University of Glasgow, Glasgow, UK ; Beatson Institute for Cancer Research, Glasgow, UK.
authors.forename: Hing Y
authors.initials: HY
authors.lastname: Leung
keywords: 5-aminoimidazole-4-carboxamide riboside (AICAR); A-769662; AMP-activated kinase (AMPK); PI3K; Prostate cancer