title: Procarcinogenic effects of cyclosporine A are mediated through the activation of TAK1/TAB1 signaling pathway.
abstract: Cyclosporine A (CsA) is an immunosuppressive drug commonly used for maintaining chronic immune suppression in organ transplant recipients. It is known that patients receiving CsA manifest increased growth of aggressive non-melanoma skin cancers. However, the underlying mechanism by which CsA augments tumor growth is not fully understood. Here, we show that CsA augments the growth of A431 epidermoid carcinoma xenograft tumors by activating tumor growth factor β-activated kinase1 (TAK1). The activation of TAK1 by CsA occurs at multiple levels by kinases ZMP, AMPK and IRAK. TAK1 forms heterodimeric complexes with TAK binding protein 1 and 2 (TAB1/TAB2) which in term activate nuclear factor κB (NFκB) and p38 MAP kinase. Transcriptional activation of NFκB is evidenced by IKKβ-mediated phosphorylation-dependent degradation of IκB and consequent nuclear translocation of p65. This also leads to enhancement in the expression of its transcriptional target genes cyclin D1, Bcl2 and COX-2. Similarly, activation of p38 leads to enhanced inflammation-related signaling shown by increased phosphorylation of MAPKAPK2 and which in turn phosphorylates its substrate HSP27. Activation of both NFκB and p38 MAP kinase provide mitogenic stimuli to augment the growth of SCCs.
authors.affiliation: Department of Dermatology, University of Alabama at Birmingham, AL 35294, USA.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Xu
authors.forename: Stephanie B
authors.initials: SB
authors.lastname: Walsh
authors.forename: Zoe M
authors.initials: ZM
authors.lastname: Verney
authors.forename: Levy
authors.initials: L
authors.lastname: Kopelovich
authors.forename: Craig A
authors.initials: CA
authors.lastname: Elmets
authors.forename: Mohammad
authors.initials: M
authors.lastname: Athar
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis*; D000818:Animals; D002273:Carcinogens / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000201:enzymology* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D020930:MAP Kinase Kinase Kinases / Q000096:biosynthesis*; D051379:Mice; D008819:Mice, Nude; D023041:Xenograft Model Antitumor Assays; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002273:Carcinogens; D016572:Cyclosporine; D007166:Immunosuppressive Agents; D020930:MAP Kinase Kinase Kinases; D000099151:MAP Kinase Kinase Kinase 7; C486300:TAB1 protein, human