Abstract
AMP-activated Protein Kinase (AMPK) activity retards growth of many types of cancers. Investigating effects of AMPK activation on breast cancer cell signaling and survival, we found that breast cancer cell lines with amplification and over-expression of HER2 or EGFR are 2- to 5-fold more sensitive to cytotoxic effects of AICAR, a canonical pharmacological activator of AMPK, than breast cancer cell lines lacking HER2 or EGFR overexpression. Paralleling effects on cell survival, AICAR leads to dose- and time-dependent inhibition of HER2 and EGFR in HER2-amplified breast cancer cells, with activation of AMPK and suppression of HER2/ EGFR activity preceding commitment to cell death. Transfection of constitutively active AMPKα also leads to decreased HER2 and EGFR phosphorylation, reduced downstream signaling associated with these receptor tyrosine kinases (RTKs), and reduced breast cancer cell growth, confirming effects of AMPK activity on HER2/ EGFR. Ensuing co-immunoprecipitation experiments demonstrated an interaction of HER2 with AMPK and an in vitro phosphorylation assay found that HER2 and EGFR contain sequences that are potential substrates for AMPK. Our results lead us to postulate that AMPK regulates HER2 and EGFR activity in HER2-amplified breast cancer cells and thus activation of AMPK might provide therapeutic benefit in such cancers.
Highlights
As the critical sensor of cellular energy, AMPactivated Protein Kinase (AMPK) is considered to be the master metabolic regulator of the eukaryotic cell [1]
We show evidence that activated AMPK negatively regulates HER2 and EGFR signaling by phosphorylating both of these proteins at novel regulatory sites, leading to inhibition of growth and survival of breast cancer cells that are dependent on these pathways
Our results suggest that AMPK activating agents have potential therapeutic benefit for HER2- and EGFRdependent breast cancers
Summary
As the critical sensor of cellular energy, AMPactivated Protein Kinase (AMPK) is considered to be the master metabolic regulator of the eukaryotic cell [1]. As a serine-threonine kinase, AMPK regulates a variety of cellular metabolic pathways with direct downstream targets that include glycogen synthase [5], HMG-CoA reductase [6], acetyl-CoA carboxylase 1 (ACC1) [7,8,9], TSC2 [10, 11], and Raptor [12]. Through these effectors, AMPK maintains energy homeostasis by turning on catabolic pathways that generate ATP while switching off anabolic pathways that consume ATP [13]. These important cell signaling interactions between AMPK and HER2/EGFR have implications with respect to prevention and treatment of cancer
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