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Inhibition of Aggressiveness of Metastatic Mouse Mammary Carcinoma Cells by the ß2-Chimaerin GAP Domain¹

Laboratory of Molecular Oncology, Quilmes National University, Bernal B1876BXD Buenos Aires, Argentina [P. L. M., G. S., D. F. A., D. E. G.], and Center for Experimental Therapeutics and Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6160 [F. C. L., M. G. K.]

The biological and functional properties of ß2-chimaerin, a novel phorbol ester/diacylglycerol receptor unrelated to protein kinase C isozymes, are largely unknown. It has previously been established that ß2-chimaerin accelerates the hydrolysis rate of GTP from Rac1 in vitro, leading to the inactivation of this GTPase, which plays important roles in the control of actin cytoskeleton organization, proliferation, motility, and invasiveness. To explore the potential role of ß2-chimaerin in invasion and metastasis, we generated stable transfectants for its catalytic domain (the ß-GAP domain) in F3II murine mammary carcinoma cells. Reduced Rac-GTP levels were observed upon stimulation with epidermal growth factor in the ß-GAP clones compared with control cells. Moreover, a marked alteration in actin polymerization in response to epidermal growth factor was observed in the ß-GAP clones, suggesting impairment of Rac-dependent responses. The ß-GAP transfectants also evidenced slower growth rates and a striking reduction in their migratory properties. Adenoviral delivery of the ß-GAP domain into F3II cells also led to reduced proliferative and migratory responses. Importantly, significant differences were found between ß-GAP transfectants and control cells regarding their tumorigenic and metastatic properties after s.c. inoculation in syngeneic BALB/c mice. Tumors originating from ß-GAP transfectants showed a significantly lower growth rate and reduced invasive ability; in addition, a lower incidence of spontaneous lung metastases was observed. Our results indicate that ß2-chimaerin impairs key steps in the metastatic cascade and provide evidence for a rational modulation of the Rac signaling pathway in cancer treatment.

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