title: AMP-activated kinase (AMPK) regulates activity of HER2 and EGFR in breast cancer.
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.
authors.affiliation: Departments of Pathology and Oncology and The Sydney Kimmel Cancer Center, The Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: Teraneh Z
authors.initials: TZ
authors.lastname: Jhaveri
authors.affiliation: Departments of Pathology and Oncology and The Sydney Kimmel Cancer Center, The Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: Juhyung
authors.initials: J
authors.lastname: Woo
authors.affiliation: Departments of Pathology and Oncology and The Sydney Kimmel Cancer Center, The Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: Xiaobin
authors.initials: X
authors.lastname: Shang
authors.affiliation: Departments of Pathology and Oncology and The Sydney Kimmel Cancer Center, The Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: Ben Ho
authors.initials: BH
authors.lastname: Park
authors.affiliation: Departments of Pathology and Oncology and The Sydney Kimmel Cancer Center, The Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Gabrielson
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D061986:MCF-7 Cells; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D034622:RNA Interference; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D012265:Ribonucleotides / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D055372:AMP-Activated Protein Kinases; D000620:Aminoimidazole Carboxamide; D066246:ErbB Receptors; D018719:Erb-b2 Receptor Tyrosine Kinases; D012265:Ribonucleotides; C031143:AICA ribonucleotide
keywords: AMP-activated protein kinase (AMPK); EGFR; HER2; cancer cell metabolism; cancer therapy