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.
Highlights
The AMP-activated protein kinase (AMPK) is a cellular energy sensor comprising of a catalytic α subunit and regulatory β and γ subunits [1]
The status of AMPK and phosphatidylinositol 3’-kinase (PI3K)/mTOR pathways was highly varied in a panel of human prostate cancer (PC) cell lines (Fig. 1A)
The variation in phospho-AMPK was independent of the level of the upstream kinase liver kinase B1 (LKB1), which was expressed at similar levels in all cell lines except in the LKB1deficient DU145 cells
Summary
The AMP-activated protein kinase (AMPK) is a cellular energy sensor comprising of a catalytic α subunit and regulatory β and γ subunits [1]. AMPK is activated when phosphorylated at Thr172 on the α subunit [1]. Two AMPK kinases have been identified that phosphorylate AMPKα Thr172, namely liver kinase B1 (LKB1) and Ca2+/calmodulin-dependent protein kinase kinase β (CaMKKβ) [2, 3]. AMP:ATP allosterically activates AMPK (binding to the AMPKγ subunit) and inhibits dephosphorylation of Thr172 in the presence of constitutive LKB1 activity. In cells expressing CaMKKβ, increased intracellular Ca2+ concentrations activate AMPK independent of changes in AMP:ATP [3]. AMPK phosphorylates multiple downstream catabolic targets to promote fatty acid oxidation and glucose uptake, www.impactjournals.com/oncoscience while anabolic processes such as fatty acid synthesis and protein synthesis tend to be suppressed [4]
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