AMPK REGULATES HER2 AND EGFR IN BREAST CANCER
Jhaveri, Teraneh Zarififar
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The AMP-activated Protein Kinase (AMPK) is a master regulator of cell metabolism, controlling fatty acid synthesis, protein synthesis and carbohydrate metabolism. Physiological states with increased AMPK activity are associated with decreased cancer incidence, leading to interest in AMPK as a potential target for cancer therapy and prevention. To explore a possible role of AMPK modulation in breast cancer therapy, we investigated how activation of AMPK affects breast cancer cell signaling and survival. Initial experiments found that breast cancer cell lines with amplification and over-expression of HER2 (BT474, HCC1419, and SKBR3) or EGFR (MDA231 and HCC1806) are 2-fold to 5-fold more sensitive to cytotoxic effects of AICAR, a canonical pharmacological activator of AMPK, than breast cancer cell lines that lack HER2 or EGFR overexpression (MCF7 and DU4475). In parallel to this activation of AMPK, we observed dose- and time-dependent inhibitory effects on phosphorylation and activity of HER2 and EGFR in these AICAR-treated, HER2-amplified breast cancer cells, with activation of AMPK and suppression of HER2/ EGFR activity preceding commitment to cell death. To further explore how AMPK activity affects HER2/ EGFR, we stably transfected HER2-amplified breast cancer cells with constitutively active AMPKα and observed that AMPK activated by this genetic manipulation also leads to decreased HER2 and EGFR phosphorylation and associated downstream signaling as well as reduced cell growth. Finally, we found that morin, a flavonoid compound previously found to inhibit fatty acid synthesis, also activates AMPK and inhibits HER2 and EGFR signaling in parallel, further supporting the link across these pathways. Metformin, another activator of AMPK, also inhibited EGFR phosphorylation in HER2-amplified breast cancer. Our results lead us to postulate that AMPK regulates HER2 and EGFR activity in HER2-amplified breast cancer cells, and activation of AMPK might provide therapeutic benefit in such cancers.