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Transforming Growth Factor-ß Receptor Inhibition Enhances Adenoviral Infectability of Carcinoma Cells via Up-Regulation of Coxsackie and Adenovirus Receptor in Conjunction with Reversal of Epithelial-Mesenchymal Transition

Divisions of ¹ Gastroenterology and ² Hematology/Oncology; ³ Cancer Research Institute; Departments of ⁴ Anatomy and ⁵ Biochemistry, University of California, San Francisco, California; ⁶ Cardiovascular Research Center, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, Hawaii; ⁷ Department of Hepatology and Gastroenterology, Charité, Campus Virchow-Klinikum, Humboldt University, Berlin, Germany; and ⁸ DNAX Research Institute of Molecular and Cellular Biology, Palo Alto, California

Correspondence: Wolfgang Michael Korn, University of California, San Francisco, Comprehensive Cancer Center, Box 0128, San Francisco, CA 94143-0128. Phone: 415-502-2844; Fax: 415-502-4787; E-mail: mkorn{at}cc.ucsf.edu.

Expression of the Coxsackie and Adenovirus Receptor (CAR) is frequently reduced in carcinomas, resulting in decreased susceptibility of such tumors to infection with therapeutic adenoviruses. Because CAR participates physiologically in the formation of tight-junction protein complexes, we examined whether molecular mechanisms known to down-regulate cell-cell adhesions cause loss of CAR expression. Transforming growth factor-ß (TGF-ß)–mediated epithelial-mesenchymal transition (EMT) is a phenomenon associated with tumor progression that is characterized by loss of epithelial-type cell-cell adhesion molecules (including E-cadherin and the tight junction protein ZO-1), gain of mesenchymal biochemical markers, such as fibronectin, and acquisition of a spindle cell phenotype. CAR expression is reduced in tumor cells that have undergone EMT in response to TGF-ß. This down-regulation results from repression of CAR gene transcription, whereas altered RNA stability and increased proteasomal protein degradation play no role. Loss of CAR expression in response to TGF-ß is accompanied by reduced susceptibility to adenovirus infection. Indeed, treatment of carcinoma cells with LY2109761, a specific pharmacologic inhibitor of TGF-ß receptor types I and II kinases, resulted in increased CAR RNA and protein levels as well as improved infectability with adenovirus. This was observed in cells induced to undergo EMT by addition of exogenous TGF-ß and in those that were transformed by endogenous autocrine/paracrine TGF-ß. These findings show down-regulation of CAR in the context of EMT and suggest that combination of therapeutic adenoviruses and TGF-ß receptor inhibitors could be an efficient anticancer strategy. (Cancer Res 2006; 66(3): 1648-57)

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