Pharmacologic regulation of AMPK in breast cancer affects cytoskeletal properties involved with microtentacle formation and re-attachment
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Kristi R. Chakrabarti1,2, Rebecca A. Whipple1, Amanda E. Boggs1,3, Lindsay K. Hessler1, Lekhana Bhandary1,2, Michele I. Vitolo1,2,4, Keyata Thompson1, Stuart S. Martin1,2,4
1University of Maryland School of Medicine, Marlene and Stewart Greenebaum National Cancer Institute Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA
2Graduate Program in Molecular Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
3Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
4Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA
Stuart S. Martin, e-mail: firstname.lastname@example.org
Keywords: AMPK, microtubule stability, microtentacles, breast cancer metastasis, re-attachment
Received: June 19, 2015 Accepted: September 11, 2015 Published: September 23, 2015
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.
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