AMPKα1 confers survival advantage of colorectal cancer cells under metabolic stress by promoting redox balance through the regulation of glutathione reductase phosphorylation

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Abstract

Patients with stage II or III colorectal cancer (CRC) exhibit various clinical outcomes after radical treatments. The 5-year survival rate was between 50 and 87%. However, the underlying mechanisms of the variation remain unclear. Here we show that AMPKα1 is overexpressed in CRC patient specimens and the high expression is correlated with poor patient survival. We further reveal a previously unrecognized function of AMPKα1, which maintains high level of reduced glutathione to keep reduction–oxidation reaction (redox) homeostasis under stress conditions, thus promoting CRC cell survival under metabolic stress in vitro and enhancing tumorigenesis in vivo. Mechanistically, AMPKα1 regulate the glutathione reductase (GSR) phosphorylation possibly through residue Thr507 which enhances its activity. Suppression of AMPKα1 by using nano-sized polymeric vector induces a favorable therapeutic effect, especially when in combination with oxaliplatin. Our study uncovers a novel function of AMPKα1 in redox regulation and identifies a promising therapeutic strategy for treatment of CRC.

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AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo.

Brandon Faubert, Gino Boily, Said Izreig … (2013)

AMPK is a metabolic sensor that helps maintain cellular energy homeostasis. Despite evidence linking AMPK with tumor suppressor functions, the role of AMPK in tumorigenesis and tumor metabolism is unknown. Here we show that AMPK negatively regulates aerobic glycolysis (the Warburg effect) in cancer cells and suppresses tumor growth in vivo. Genetic ablation of the α1 catalytic subunit of AMPK accelerates Myc-induced lymphomagenesis. Inactivation of AMPKα in both transformed and nontransformed cells promotes a metabolic shift to aerobic glycolysis, increased allocation of glucose carbon into lipids, and biomass accumulation. These metabolic effects require normoxic stabilization of the hypoxia-inducible factor-1α (HIF-1α), as silencing HIF-1α reverses the shift to aerobic glycolysis and the biosynthetic and proliferative advantages conferred by reduced AMPKα signaling. Together our findings suggest that AMPK activity opposes tumor development and that its loss fosters tumor progression in part by regulating cellular metabolic pathways that support cell growth and proliferation. Copyright © 2013 Elsevier Inc. All rights reserved.

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Global Phosphoproteomic Analysis of Human Skeletal Muscle Reveals a Network of Exercise-Regulated Kinases and AMPK Substrates.

Nolan Hoffman, Benjamin Parker, Rima Chaudhuri … (2015)

Exercise is essential in regulating energy metabolism and whole-body insulin sensitivity. To explore the exercise signaling network, we undertook a global analysis of protein phosphorylation in human skeletal muscle biopsies from untrained healthy males before and after a single high-intensity exercise bout, revealing 1,004 unique exercise-regulated phosphosites on 562 proteins. These included substrates of known exercise-regulated kinases (AMPK, PKA, CaMK, MAPK, mTOR), yet the majority of kinases and substrate phosphosites have not previously been implicated in exercise signaling. Given the importance of AMPK in exercise-regulated metabolism, we performed a targeted in vitro AMPK screen and employed machine learning to predict exercise-regulated AMPK substrates. We validated eight predicted AMPK substrates, including AKAP1, using targeted phosphoproteomics. Functional characterization revealed an undescribed role for AMPK-dependent phosphorylation of AKAP1 in mitochondrial respiration. These data expose the unexplored complexity of acute exercise signaling and provide insights into the role of AMPK in mitochondrial biochemistry.

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The AMP-activated protein kinase (AMPK) and cancer: many faces of a metabolic regulator.

Brandon Faubert, Emma Vincent, Maya Poffenberger … (2015)

The AMP-activated protein kinase (AMPK) is a central regulator of cellular metabolism and energy homeostasis in mammalian tissues. Pertinent to cancer biology is the fact that AMPK is situated in the center of a signaling network involving established tumor suppressors including LKB1, TSC2 and p53. However, recent research suggests that AMPK can exert pro- or anti-tumorigenic roles in cancer depending on context. Loss of AMPK activity has been observed in several tumor types, and can cooperate with oncogenic drivers to reprogram tumor cell metabolism and enhance cell growth and proliferation. However, AMPK activation can also provide a growth advantage to tumor cells by regulating cellular metabolic plasticity, thus providing tumor cells the flexibility to adapt to metabolic stress. Here we discuss the contextual nature of the "two faces" of AMPK in cancer, and discuss the rationale and context for employing AMPK activators versus inhibitors for cancer therapy.