Novel Metabolic Regulation of Invadopodia and Invasion by Acetyl-CoA Carboxylase and Lipogenesis

Invadopodia are membrane protrusions that facilitate matrix degradation and cellular invasion. Although cellular lipids have been implicated in several aspects of invadopodia assembly and function, the contribution of de novo fatty acid and phospholipid synthesis has not been elucidated. The data in this dissertation demonstrates the requirement of fatty acid synthesis for the generation and function of invadopodia. Inhibition of acetyl-CoA carboxylase (ACC), the rate-limiting step of fatty acid synthesis, reduced invadopodia incidence in Src-transformed 3T3 (3T3-Src) cells. Blocking ACC or fatty acid synthase (FASN) activity also altered pathway activity and cellular phospholipid profiles, including that of phosphatidylcholine (PC). Exogenous supplementation with fatty acid or PC following ACC inhibition was sufficient to restore both the formation and gelatin-degrading capabilities of invadopodia in 3T3-Src cells. Moreover, the lipid-dependent requirement for ACC activity during cellular invasion was also observed in both 3T3-Src cells and human cancer cells. The generation of invadopodia was also regulated by the phosphorylation status of ACC, as activation of AMPK by fenofibrate or AICAR resulted in increases in p-ACC and invadopodia loss. Cumulatively, these data provide the first evidence that de novo fatty acid synthesis and specific PC species are required for invadopodia and the invasive capacity of transformed cells and suggests a novel metabolic regulation of these processes.

Grantor dc:publisher

Wake Forest University

Year dc:date.issued

2011

Author dc:creator

• Scott, Kristen Elizabeth Norman

• Acetyl-CoA Carboxylase

Language dc:language.iso

en

Handle dc:identifier.uri

http://hdl.handle.net/10339/36444

OAI identifier oai:identifier

oai:wakespace.lib.wfu.edu:10339/36444