title: Pharmacologic regulation of AMPK in breast cancer affects cytoskeletal properties involved with microtentacle formation and re-attachment.
abstract: The presence of tumor cells in the circulation is associated with a higher risk of metastasis in patients with breast cancer. Circulating breast tumor cells use tubulin-based structures known as microtentacles (McTNs) to re-attach to endothelial cells and arrest in distant organs. McTN formation is dependent on the opposing cytoskeletal forces of stable microtubules and the actin network. AMP-activated protein kinase (AMPK) is a cellular metabolic regulator that can alter actin and microtubule organization in epithelial cells. We report that AMPK can regulate the cytoskeleton of breast cancer cells in both attached and suspended conditions. We tested the effects of AMPK on microtubule stability and the actin-severing protein, cofilin. AMPK inhibition with compound c increased both microtubule stability and cofilin activation, which also resulted in higher McTN formation and re-attachment. Conversely, AMPK activation with A-769662 decreased microtubule stability and cofilin activation with concurrent decreases in McTN formation and cell re-attachment. This data shows for the first time that AMPK shifts the balance of cytoskeletal forces in suspended breast cancer cells, which affect their ability to form McTNs and re-attach. These results support a model where AMPK activators may be used therapeutically to reduce the metastatic efficiency of breast tumor cells.
authors.affiliation: University of Maryland School of Medicine, Marlene and Stewart Greenebaum National Cancer Institute Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.|Graduate Program in Molecular Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Kristi R
authors.initials: KR
authors.lastname: Chakrabarti
authors.affiliation: University of Maryland School of Medicine, Marlene and Stewart Greenebaum National Cancer Institute Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Whipple
authors.affiliation: University of Maryland School of Medicine, Marlene and Stewart Greenebaum National Cancer Institute Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.|Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Amanda E
authors.initials: AE
authors.lastname: Boggs
authors.affiliation: University of Maryland School of Medicine, Marlene and Stewart Greenebaum National Cancer Institute Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Lindsay K
authors.initials: LK
authors.lastname: Hessler
authors.affiliation: University of Maryland School of Medicine, Marlene and Stewart Greenebaum National Cancer Institute Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.|Graduate Program in Molecular Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Lekhana
authors.initials: L
authors.lastname: Bhandary
authors.affiliation: University of Maryland School of Medicine, Marlene and Stewart Greenebaum National Cancer Institute Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.|Graduate Program in Molecular Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.|Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Michele I
authors.initials: MI
authors.lastname: Vitolo
authors.affiliation: University of Maryland School of Medicine, Marlene and Stewart Greenebaum National Cancer Institute Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Keyata
authors.initials: K
authors.lastname: Thompson
authors.affiliation: University of Maryland School of Medicine, Marlene and Stewart Greenebaum National Cancer Institute Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.|Graduate Program in Molecular Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.|Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Stuart S
authors.initials: SS
authors.lastname: Martin
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D001713:Biphenyl Compounds; D001943:Breast Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D003599:Cytoskeleton / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D008870:Microtubules / Q000378:metabolism*; D009362:Neoplasm Metastasis; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011753:Pyrones / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology
chemical_list: D001713:Biphenyl Compounds; D011720:Pyrazoles; D011743:Pyrimidines; D011753:Pyrones; D013876:Thiophenes; C516138:dorsomorphin; D055372:AMP-Activated Protein Kinases; C512408:4-hydroxy-3-(4-(2-hydroxyphenyl)phenyl)-6-oxo-7H-thieno(2,3-b)pyridine-5-carbonitrile
keywords: AMPK; breast cancer metastasis; microtentacles; microtubule stability; re-attachment