Abstract
Invadopodia are membrane protrusions that facilitate matrix degradation and cellular invasion. Although lipids have been implicated in several aspects of invadopodia formation, the contributions of de novo fatty acid synthesis and lipogenesis have not been defined. Inhibition of acetyl-CoA carboxylase 1 (ACC1), the committed step of fatty acid synthesis, reduced invadopodia formation in Src-transformed 3T3 (3T3-Src) cells, and also decreased the ability to degrade gelatin. Inhibition of fatty acid synthesis through AMP-activated kinase (AMPK) activation and ACC phosphorylation also decreased invadopodia incidence. The addition of exogenous 16∶0 and 18∶1 fatty acid, products of de novo fatty acid synthesis, restored invadopodia and gelatin degradation to cells with decreased ACC1 activity. Pharmacological inhibition of ACC also altered the phospholipid profile of 3T3-Src cells, with the majority of changes occurring in the phosphatidylcholine (PC) species. Exogenous supplementation with the most abundant PC species, 34∶1 PC, restored invadopodia incidence, the ability to degrade gelatin and the ability to invade through matrigel to cells deficient in ACC1 activity. On the other hand, 30∶0 PC did not restore invadopodia and 36∶2 PC only restored invadopodia incidence and gelatin degradation, but not cellular invasion through matrigel. Pharmacological inhibition of ACC also reduced the ability of MDA-MB-231 breast, Snb19 glioblastoma, and PC-3 prostate cancer cells to invade through matrigel. Invasion of PC-3 cells through matrigel was also restored by 34∶1 PC supplementation. Collectively, the data elucidate the novel metabolic regulation of invadopodia and the invasive process by de novo fatty acid synthesis and lipogenesis.
Highlights
Podosomes and invadopodia are membrane protrusions at focalized sites of polymerized actin that coordinate the invasive properties or normal and tumor cells, respectively [1]
To determine whether fatty acid synthesis has a role in Src mediated invadopodia formation, the expression and activity of the fatty acid synthesis pathway was determined in 3T3 cells and 3T3 cells transformed with constitutively active Src (3T3-Src) [38]
Even though de novo fatty acid synthesis is clearly associated with membrane biogenesis, the mechanism by which the pathway regulates the processes of tumor cell invasion and migration has remained undefined
Summary
Podosomes and invadopodia are membrane protrusions at focalized sites of polymerized actin that coordinate the invasive properties or normal and tumor cells, respectively [1]. In addition to polymerized actin, both structures comprise a complex assortment of proteins including actin-modifying proteins, integrins, proteases, multiple kinases, and several scaffolding proteins [2]. The integration of these components facilitates the invasive process through coordinated proteolysis of the extracellular matrix [3]. Podosomes have been visualized on invading cells ex vivo and disruption of podosome architecture decreases the ability of cells to invade [1,4] Because of their complex makeup, both structures can be regulated through multiple mechanisms including, but not limited to, kinase signaling and reactive oxygen species [1,5]. Given the complex architecture of podosomes and invadopodia it is likely that other processes underlying podosome and invadopodia construction remain to be elucidated
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