Abstract
Cellular motility is the basis for cancer cell invasion and metastasis. In the case of breast cancer, the most common type of cancer among women, metastasis represents the most devastating stage of the disease. The central role of cellular motility in cancer development emphasizes the importance of understanding the specific mechanisms involved in this process. In this context, tumor development and metastasis would be the consequence of a loss or defect of the mechanisms that control cytoskeletal remodeling. Profilin I belongs to a family of small actin binding proteins that are thought to assist in actin filament elongation at the leading edge of migrating cells. Traditionally, Profilin I has been considered to be an essential control element for actin polymerization and cell migration. Expression of Profilin I is down-regulated in breast and various other cancer cells. In MDA-MB-231 cells, a breast cancer cell line, further inhibition of Profilin I expression promotes hypermotility and metastatic spread, a finding that contrasts with the proposed role of Profilin in enhancing polymerization. In this report, we have taken advantage of the fluorescence recovery after photobleaching (FRAP) of GFP-actin to quantify and compare actin dynamics at the leading edge level in both cancer and non-cancer cell models. Our results suggest that (i) a high level of actin dynamics (i.e., a large mobile fraction of actin filaments and a fast turnover) is a common characteristic of some cancer cells; (ii) actin polymerization shows a high degree of independence from the presence of extracellular growth factors; and (iii) our results also corroborate the role of Profilin I in regulating actin polymerization, as raising the intracellular levels of Profilin I decreased the mobile fraction ratio of actin filaments and slowed their polymerization rate; furthermore, increased Profilin levels also led to reduced individual cell velocity and directionality.
Highlights
Cellular motility is a complex process that occurs in all cell types [1]
The second slower component was driven by actin polymerization [47,48], which was confirmed by the addition of 90 nM cytochalasin D to the culture media five minutes prior to the fluorescence recovery after photobleaching (FRAP) experiment
Our results indicate that (1) The tumor cell lines examined present a high motility actin; (2) MDA-MB-231 actin dynamics at the leading edge are independent of extracellular growth factors; and (3) Profilin I negatively regulates actin polymerization, reducing actin mobile fraction and slowing the recovery time
Summary
Cellular motility is a complex process that occurs in all cell types [1]. Migration over a flat surface involves the protrusion of a thin membrane mantle, the lamella, filled with an intricate actin branched network. The force for the membrane protrusion and extension is provided by controlled and restricted actin polymerization at the closest edge of the membrane, the so-called leading edge. Actin filaments are polarized with their barbed end (or plus end) pointing towards the membrane [2], which is pushed by the filaments, forcing the extension of the lamella. Close regulation of cell migration is essential for development, wound healing and immune responses, whereas aberrant and uncontrolled cell motility is a recurrent feature in several types of cancer cells
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