title: Inhibiting cycloxygenase and ornithine decarboxylase by diclofenac and alpha-difluoromethylornithine blocks cutaneous SCCs by targeting Akt-ERK axis.
abstract: Non-melanoma skin cancer (NMSC) is the most common type of skin cancer in Caucasian populations. Its increasing incidence has been a major public health concern. Elevated expressions of ODC and COX-2 are associated with both murine and human NMSCs. Inhibition of these molecular targets singly employing their respective small molecule inhibitors showed limited success. Here, we show that combined blockade of ODC and COX-2 using their potent inhibitors, DFMO and diclofenac respectively abrogates growth of A431 epidermal xenograft tumors in nu/nu mice by more than 90%. The tumor growth inhibition was associated with a diminution in the proliferation and enhancement in apoptosis. The proliferation markers such as PCNA and cyclin D1 were reduced. TUNEL-positive apoptotic cells and cleaved caspase-3 were increased in the residual tumors. These agents also manifested direct target-unrelated effects. Reduced expression of phosphorylated MAPKAP-2, ERK, and Akt (ser(473) & thr(308)) were noticed. The mechanism by which combined inhibition of ODC/COX attenuated tumor growth and invasion involved reduction in EMT. Akt activation by ODC+COX-2 over-expression was the key player in this regard as Akt inhibition manifested effects similar to those observed by the combined inhibition of ODC+COX-2 whereas forced over-expression of Akt resisted against DFMO+diclofenac treatment. These data suggest that ODC+COX-2 over-expression together leads to pathogenesis of aggressive and invasive cutaneous carcinomas by activating Akt signaling pathway, which through augmenting EMT contributes to tumor invasion.
authors.affiliation: Department of Dermatology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Aadithya
authors.initials: A
authors.lastname: Arumugam
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Weng
authors.forename: Sarang S
authors.initials: SS
authors.lastname: Talwelkar
authors.forename: Sandeep C
authors.initials: SC
authors.lastname: Chaudhary
authors.forename: Levy
authors.initials: L
authors.lastname: Kopelovich
authors.forename: Craig A
authors.initials: CA
authors.lastname: Elmets
authors.forename: Farrukh
authors.initials: F
authors.lastname: Afaq
authors.forename: Mohammad
authors.initials: M
authors.lastname: Athar
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism; D002352:Carrier Proteins / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D004008:Diclofenac / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D000518:Eflornithine / Q000494:pharmacology*; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D008819:Mice, Nude; D009955:Ornithine Decarboxylase / Q000378:metabolism; D065108:Ornithine Decarboxylase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D052246:Cyclooxygenase 2 Inhibitors; D065108:Ornithine Decarboxylase Inhibitors; C039317:ornithine decarboxylase antizyme inhibitor; D004008:Diclofenac; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D051057:Proto-Oncogene Proteins c-akt; D009955:Ornithine Decarboxylase; D000518:Eflornithine