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 nonmelanoma 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.

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

“…CsA treatment significantly increased the levels of proliferation markers cyclin D1 and proliferating cell nuclear antigen (PCNA) as compared to vehicle-treated control group (Figure 2A and B) confirming our earlier observation [16, 19]. However, administration of inhibitors of p38 or Akt alone or in combination to CsA-treated animals significantly decreased the expression of these proteins (Figure 2A and B and Suppl.…”

“…We also showed that CsA by regulating TGFβ-dependent signaling pathway promotes EMT and modulate invasive potential of cutaneous SCCs [16]. In this regard, our studies further demonstrated an involvement of TAK1/TAB1 signaling pathway, which by regulating MAPK and Akt augment cancer cell survival [19]. Here, we demonstrated that combined inhibition of p38 and Akt signaling pathways abrogates CsA-mediated cancer progression.…”

“…The lysates were centrifuged at 10,000 r.p.m for 15 min at 4 °C. The supernatant obtained was used for further analysis as described earlier [19]. …”

“…We also showed that CsA alters the functioning of mitochondria and blocks the mitochondrial permeability pore (MPP) opening, thereby interfering with the ability of these cells to undergo apoptosis [18]. Additional studies from our laboratory demonstrated that CsA treatment enhances the growth of SCCs by activating nuclear factor κB (NF κB) and p38 MAP kinase pathways and regulating tumor growth factor β-activated kinase 1 (TAK1) [19]. …”

HPV Carcinomas in Immunocompromised Patients

“…With respect to skin cancer, CNIs have inhibitory effects on p53 and E-cadherin (tumor suppressors) which permit keratinocyte transformation and skin carcinogenesis [70]. Additionally, CNIs inhibit the DNA repair required to prevent transformation of UV damage to carcinogenesis, which implies a CNI-dependent oncogenic synergy between UV skin damage and immunosuppression [71].…”