Abstract 1098: Mechano-molecular imaging of the role of COX-2 in cell traction force.

Abstract

Abstract The cytoplasmic enzyme cyclooxygenase (COX)-2 and its secondary lipid byproducts are critical determinants of cancer cell invasion and metastasis. Poorly differentiated MDA-MB-231 human breast cancer cells stably expressing COX-2 shRNA exhibit marked attenuation in their ability to secrete secondary lipid mediator products of the COX reaction, as well as invade and degrade reconstituted extracellular matrix in vitro. COX-2-silenced cells inoculated in vivo show significant reduction of tumor growth and extrapulmonary colonization than their parental counterpart. Based on compelling evidence for the positive correlation between cancer invasion and cell traction force, here we interrogated the mechanistic role for COX-2 in mediating this physical force and imaged the spatiotemporal distribution of contractile stress arising at the interface between each adherent cell and its substrate. Over a physiological range of substrate stiffness, COX-2-silenced MDA-MB-231 cells exhibited a smaller spreading area and a lower cell traction force than their highly metastatic, parental counterpart. Strikingly, unlike COX-2-silenced cells, COX-2-high parental MDA-MB-231 cells showed progressive increases in cell spreading area and traction force with increasing substrate rigidity. Cell spreading and traction force in COX-2-silenced cells were restored with an exogenous addition of COX-2-derived PGE2, however. COX-2-high MDA-MB-231 cells also showed increases in the expression of mechanosensitive integrin β1, and not β3, with increasing substrate rigidity. Consistent with these physical attributes, COX-2-silenced cells expressed a 4.6-fold reduction of the transcript coding for RhoJ, a member of the family of Rho GTPases, and displayed a slower remodeling dynamics of the cytoskeleton (CSK). To our knowledge this is the first report linking the expression of COX-2 with increased cell traction force and CSK remodeling in a highly metastatic human breast cancer. Citation Format: A Rum Yoon, Ioannis Stasinopoulos, Steven An, Zaver M. Bhujwalla. Mechano-molecular imaging of the role of COX-2 in cell traction force. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1098. doi:10.1158/1538-7445.AM2013-1098