title: Cyclooxygenase-2 induction and prostaglandin E2 accumulation in squamous cell carcinoma as a consequence of epidermal growth factor receptor activation by imatinib mesylate.
abstract: Imatinib mesylate is a novel anti-tumor agent useful in the clinical management of chronic myelogenous leukemia and gastrointestinal stromal tumors with minimal toxicity relative to other forms of cancer therapy. Its clinical activity and minimal toxicity are related to specific inhibition of cellular targets including BCR-ABL, platelet-derived growth factor receptor and c-kit kinases, resulting in the collapse of downstream signaling cascades important for transformation. In some patients, unexpected toxicities arise that are not associated with inhibition of any known cellular imatinib target. In this report, we investigated the effects of imatinib on squamous carcinoma cell signaling. Imatinib induced expression of COX-2 in a dose-dependent manner with concomitant accumulation of prostaglandin E2. COX-2 induction by imatinib was initiated through epidermal growth factor (EGF) receptor kinase activation and downstream signaling through mitogenic-activated protein kinase. COX-2 induction by imatinib was blocked by MEK1 or EGF receptor inhibition. Imatinib did not activate stressor cytokine-signaling pathways (p38 kinase, nuclear factor-kB nuclear translocation) or affect COX-1 expression. Imatinib failed to activate EGF receptor signals in other tumor types, suggesting that COX-2 induction in imatinib-treated cells is mediated through release of autocrine factors expressed or activated in squamous tumors. COX-2 induction by imatinib in squamous tumors derived from the head and neck region is unique with respect to other target-specific agents and may represent one of the unintended toxic effects of imatinib described in some patients.
authors.affiliation: Department of Thoracic and Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA. fmjohns@mdanderson.org
authors.forename: Faye M
authors.initials: FM
authors.lastname: Johnson
authors.forename: Peiying
authors.initials: P
authors.lastname: Yang
authors.forename: Robert A
authors.initials: RA
authors.lastname: Newman
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Donato
mesh_terms: D000891:Anti-Infective Agents, Local / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D016718:Arachidonic Acid / Q000378:metabolism; D001549:Benzamides; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism*; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D015777:Eicosanoids / Q000378:metabolism; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000378:metabolism*; D005840:Gentian Violet / Q000494:pharmacology; D006258:Head and Neck Neoplasms / Q000188:drug therapy*; D006801:Humans; D000068877:Imatinib Mesylate; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D008565:Membrane Proteins; D010879:Piperazines / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D000891:Anti-Infective Agents, Local; D000970:Antineoplastic Agents; D001549:Benzamides; D015777:Eicosanoids; D008565:Membrane Proteins; D010879:Piperazines; D011743:Pyrimidines; D016718:Arachidonic Acid; D000068877:Imatinib Mesylate; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D066246:ErbB Receptors; D048369:MAP Kinase Kinase 1; D005840:Gentian Violet; D015232:Dinoprostone