Combined inhibition of p38 and Akt signaling pathways abrogates cyclosporine A-mediated pathogenesis of aggressive skin SCCs

Abstract

Non-melanoma skin cancers (NMSCs) are the most common neoplasm in organ transplant recipients (OTRs). These cancers are more invasive and metastatic as compared to those developed in normal cohorts. Previously, we have shown that immunosuppressive drug, cyclosporine A (CsA) directly alters tumor phenotype of cutaneous squamous cell carcinomas (SCCs) by activating TGF-β and TAK1/TAB1 signaling pathways. Here, we identified novel molecular targets for the therapeutic intervention of these SCCs. We observed that combined blockade of Akt and p38 kinases-dependent signaling pathways in CsA-promoted human epidermoid carcinoma A431 xenograft tumors abrogated their growth by more than 90%. This diminution in tumor growth was accompanied by a significant decrease in proliferation and an increase in apoptosis. The residual tumors following the combined treatment with Akt inhibitor triciribine and p38 inhibitors SB-203580 showed significantly diminished expression of phosphorylated Akt and p38 and these tumors were less invasive and highly differentiated. Diminished tumor invasiveness was associated with the reduced epithelial–mesenchymal transition as ascertained by the enhanced E-cadherin and reduced vimentin and N-cadherin expression. Consistently, these tumors also manifested reduced MMP-2/9. The decreased p-Akt expression was accompanied by a significant reduction in p-mTOR. These data provide first important combinatorial pharmacological approach to block the pathogenesis of CsA-induced highly aggressive cutaneous neoplasm in OTRs.

Retinoid X Receptor Agonists Upregulate Genes Responsible for the Biosynthesis of All-Trans-Retinoic Acid in Human Epidermis

“…These medications suppress the host immune response that has evolved to protect against the growth and development of non-melanoma skin cancers. They also promote epithelial-mesenchymal transition by activating the TGFβ signal transduction pathway in epidermal keratinocytes [ 82 – 84 ]. As shown in this study, bexarotene (Targretin), the only rexinoid approved by the FDA, induces the same panel of ATRA-sensitive genes as UAB30, but with a greater potency.…”

REGγ is critical for skin carcinogenesis by modulating the Wnt/β-catenin pathway

“…It is worth emphasizing that REGg-KO mice also develop a few tumours after 20 weeks of TPA treatments, but with delayed onset, in agreement with the importance of MAPK/p38 signalling for additional targets, such as Stat3, AKT and NFkB 32 . Indeed, combined inhibition of p38 and AKT signalling pathways abrogates cyclosporine A-mediated pathogenesis of aggressive skin SCCs 33 . Thus, additional studies are necessary to elucidate the cross-talk between the p38/MAPK signalling pathway and other signalling molecules during skin carcinogenesis in REGg-deficient mice.…”

Inhibiting Cycloxygenase and Ornithine Decarboxylase by Diclofenac and Alpha-Difluoromethylornithine Blocks Cutaneous SCCs by Targeting Akt-ERK Axis

“…Akt, a serine/threonine protein kinase is activated by phosphorylation and protects cells from apoptosis by directly phosphorylating and inactivating proapoptotic protein targets [40] . Akt activation is known to be involved in the pathogenesis of cutaneous SCCs [41] , [42] . In the present study, DFMO treatment failed to decrease the levels of p-Akt conferring resistance to apoptosis in A431 xenograft tumors.…”