DDR1 belongs to a small family of receptor tyrosine kinases that contain an extracellular domain of 160 amino acids exhibiting strong homology to the Dictyostelium discoideum protein discoidin 1. Various types of collagen have been identified as ligands capable of activating DDR1. The activation process is unique in that it is slow but sustained over long periods with no down-regulation by endocytosis or receptor degradation. DDR1 has been found to play a role in cell attachment, migration, cell survival and proliferation. Overexpression of this receptor has been reported in lung, brain, mammary and ovarian cancers suggestive of its role in tumorigenesis. However little information is available 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. Knock-down of DDDR1 mediated Cox-2 induction using shRNA results in increased chemosensitivity. Our results also show that DDR1 mediated Cox-2 induction is NFκB dependent. DDR1 activates the NFκB pathway and blocking the activation of NFκB by using IκB super-repressor mutant results in failure of DDR1 to induce Cox-2 resulting in enhanced chemosensitivity. For DDR1 mediated NFκB activation the upstream activating kinases of the NFκB pathway, IKKβ and IKKγ, are essential while IKKα seems to be dispensable. Moreover, DDR1 mediated NFκB activation results in induction of other anti-apoptotic targets of NFκB such as XIAP. Depletion of DDR1 expression via RNAi approach significantly enhances chemosensitivity to genotoxic drugs as well as reduces the migration potential and invasiveness of cancer cells. Our xenograft studies in nude mice show that DDR1 overexpression enhances the tumorigenicity of cancer cells by promoting angiogenesis while knock down of DDR1 expression in cancer cells reduce their tumorigenicity. Thus, our study provides a novel mechanistic insight into the role of DDR1 with implications for cancer therapeutics.
[Proc Amer Assoc Cancer Res, Volume 47, 2006]