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Discoidin Domain Receptor 1 Receptor Tyrosine Kinase Induces Cyclooxygenase-2 and Promotes Chemoresistance through Nuclear Factor-B Pathway Activation

¹ Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts; ² Curonix, Inc., Seoul, South Korea; and ³ Department of Oncological Sciences, Mount Sinai School of Medicine, New York, New York

Requests for reprints: Sam W. Lee, Cutaneous Biology Research Center, Massachusetts General Hospital, Building 149, 13th Street, Charlestown, MA 02129. Phone: 617-726-6691; Fax: 617-643-2334; E-mail: sam.lee{at}cbrc2.mgh.harvard.edu.

Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase activated by various types of collagens and is known to play a role in cell attachment, migration, survival, and proliferation. However, little is known about the molecular mechanism(s) underlying the role of DDR1 in cancer. We report here that DDR1 induces cyclooxygenase-2 (Cox-2) expression resulting in enhanced chemoresistance. Depletion of DDR1-mediated Cox-2 induction using short hairpin RNA (shRNA) results in increased chemosensitivity. We also show that DDR1 activates the nuclear factor-B (NF-B) pathway and blocking this activation by an IB superrepressor mutant results in the ablation of DDR1-induced Cox-2, leading to enhanced chemosensitivity, indicating that DDR1-mediated Cox-2 induction is NF-B dependent. We identify the upstream activating kinases of the NF-B pathway, IKKß and IKK, as essential for DDR1-mediated NF-B activation, whereas IKK seems to be dispensable. Finally, shRNA-mediated inhibition of DDR1 expression significantly enhanced chemosensitivity to genotoxic drugs in breast cancer cells. Thus, DDR1 signaling provides a novel target for therapeutic intervention with the prosurvival/antiapoptotic machinery of tumor cells. (Cancer Res 2006; 66(16): 8123-30)

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