Prostaglandin E2 synergistically enhances receptor tyrosine kinase-dependent signaling system in colon cancer cells.
Cyclooxygenase (COX)-generated prostaglandin E(2) (PGE(2)) plays critical roles in colorectal carcinogenesis. Recently, we have shown that PGE(2) and transforming growth factor-alpha synergistically induces the expression of amphiregulin (AR) in colon cancer cells (Shao, J., Evers, B. M., and Sheng, H. (2003) Cancer Res. 63, 5218-5223). In this study, we demonstrated synergistic actions of PGE(2) and the receptor tyrosine kinase signaling system in AR expression and in tumorigenic potential of colon cancer cells. Activation of the Ras/Raf/MAPK pathway induced AR transcription in colon cancer LS-174 cells that was enhanced by PGE(2) in a synergistic fashion. The cAMP-responsive element within the AR promoter was required for the synergistic activation of AR transcription. An Sp1 element was responsible for the basal transcription of AR and significantly enhanced the synergy between PGE(2) and the epidermal growth factor receptor (EGFR) signaling system. Furthermore, activation of both PGE(2) and EGFR signaling pathways synergistically promoted the growth and migration of colon cancer cells. Our results suggest that COX-2/PGE(2) may exert pro-oncogenic effects through synergistic induction of receptor tyrosine kinase-dependent signaling pathway, thus, provide a novel mechanism for the combinatorial treatment of colonic neoplasms targeting both COX-2/PGE(2) and the EGFR system that has demonstrated remarkable advantages.
Shao
Jinyi
J
Department of Surgery and Sealy Center for Cancer Cell Biology, University of Texas Medical Branch, Galveston Texas 77555, USA.
Evers
B Mark
BM
Sheng
Hongmiao
H
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects; D003110:Colonic Neoplasms; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000494:pharmacology*; D004357:Drug Synergism; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology; D008565:Membrane Proteins; D011401:Promoter Regions, Genetic / Q000502:physiology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D020218:Response Elements / Q000502:physiology; D016329:Sp1 Transcription Factor / Q000378:metabolism; D016211:Transforming Growth Factor alpha / Q000494:pharmacology*; D018631:ras Proteins / Q000378:metabolism
D000970:Antineoplastic Agents; D017362:Cyclic AMP Response Element-Binding Protein; D007527:Isoenzymes; D008565:Membrane Proteins; D016329:Sp1 Transcription Factor; D016211:Transforming Growth Factor alpha; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D066246:ErbB Receptors; D019908:Proto-Oncogene Proteins c-raf; D018631:ras Proteins; D015232:Dinoprostone