Discoidin domain receptor 1 receptor tyrosine kinase induces cyclooxygenase-2 and promotes chemoresistance through nuclear factor-kappaB pathway activation.
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-kappaB (NF-kappaB) pathway and blocking this activation by an I kappaB superrepressor mutant results in the ablation of DDR1-induced Cox-2, leading to enhanced chemosensitivity, indicating that DDR1-mediated Cox-2 induction is NF-kappaB dependent. We identify the upstream activating kinases of the NF-kappaB pathway, IKK beta and IKK gamma, as essential for DDR1-mediated NF-kappaB activation, whereas IKK alpha 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.
Das
Sanjeev
S
Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
Ongusaha
Pat P
PP
Yang
Yoon Sun
YS
Park
Jin-Mo
JM
Aaronson
Stuart A
SA
Lee
Sam W
SW
D017209:Apoptosis; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000235:genetics*; D004249:DNA Damage; D000070818:Discoidin Domain Receptors; D004351:Drug Resistance; D004790:Enzyme Induction; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D006801:Humans; D016328:NF-kappa B / Q000502:physiology*; D012334:RNA, Neoplasm / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D011975:Receptors, Mitogen / Q000378:metabolism*; D014162:Transfection
D016328:NF-kappa B; D012334:RNA, Neoplasm; D011975:Receptors, Mitogen; D051546:Cyclooxygenase 2; D000070818:Discoidin Domain Receptors; D020794:Receptor Protein-Tyrosine Kinases