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.
Highlights
Primary breast cancers shed millions of cells into circulation during the early steps of tumor formation
A pharmacological approach was utilized to understand the effects of altering the adenosine monophosphateactivated protein kinase (AMPK) pathway on the cytoskeletal properties of breast cancer cells
This study investigates the role of the cellular metabolic regulator, AMPK, on the cytoskeletal properties of human breast tumor cells
Summary
Primary breast cancers shed millions of cells into circulation during the early steps of tumor formation. These single disseminated cells, known as circulating tumor cells (CTCs), can go on to invade distant sites and cause metastatic disease [1]. While metastasis remains the leading cause of mortality in patients diagnosed with breast cancer, there are currently no treatments to target the metastatic cascade [4]. A great deal of work has been done to study the effects of AMPK on primary tumor formation, its effects on breast cancer metastasis are still largely unknown
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