Cyclosporine induces cancer progression by a cell-autonomous mechanism

Abstract

Malignancy is a common and dreaded complication following organ transplantation. The high incidence of neoplasm and its aggressive progression, which are associated with immunosuppressive therapy, are thought to be due to the resulting impairment of the organ recipient's immune-surveillance system. Here we report a mechanism for the heightened malignancy that is independent of host immunity. We show that cyclosporine (cyclosporin A), an immunosuppressant that has had a major impact on improving patient outcome following organ transplantation, induces phenotypic changes, including invasiveness of non-transformed cells, by a cell-autonomous mechanism. Our studies show that cyclosporine treatment of adenocarcinoma cells results in striking morphological alterations, including membrane ruffling and numerous pseudopodial protrusions, increased cell motility, and anchorage-independent (invasive) growth. These changes are prevented by treatment with monoclonal antibodies directed at transforming growth factor-beta (TGF-beta). In vivo, cyclosporine enhances tumour growth in immunodeficient SCID-beige mice; anti-TGF-beta monoclonal antibodies but not control antibodies prevent the cyclosporine-induced increase in the number of metastases. Our findings suggest that immunosuppressants like cyclosporine can promote cancer progression by a direct cellular effect that is independent of its effect on the host's immune cells, and that cyclosporine-induced TGF-beta production is involved in this.

Mitochondrial stress-induced calcium signaling, phenotypic changes and invasive behavior in human lung carcinoma A549 cells

“…The reverted cells, on the other hand, appeared more rounded and closer to the control cells in morphology (Figure 2c). The morphological changes were similar to those in cyclosporin-treated cells described by Hojo et al (1999), which were also shown to be more invasive. As shown in Figure 2d, the mtDNA-depleted cells exhibited a markedly slower growth rate as compared to control cells, which is characteristic of r 0 and r 7 cells (Desjardins et al, 1985;King and Attardi, 1989;Miranda et al, 1999).…”

“…Matrix protease cathepsin L is an important marker for invasive tumors (Cuvier et al, 1997;Kim et al, 1998). Similarly, TGFb has been shown to be important in inducing the invasive behavior in several tumor cells including A549 (Hojo et al, 1999;Fujimoto et al, 2001;Hata, 2001). Immunoblot analysis of post-nuclear protein fraction (Figure 5a) showed that the levels of both cathepsin L and TGFb are three to six times higher in mtDNA-depleted cells.…”

“…We chose the human pulmonary adenocarcinoma cell line A549 for this study since these cells are less invasive, though they produce localized tumors in nude mice (Mooradian et al, 1992;Hojo et al, 1999). We generated mtDNA-depleted A549 cell line by culturing cells in the presence of 100 ng/ml of ethidium bromide (EtBr) for 30 division cycles, essentially as described before for C2C12 rhabdomyoblasts (Biswas et al, 1999).…”

Regulation of the tyrosine kinase Itk by the peptidyl-prolyl isomerase cyclophilin A

“…These findings are provocative in light of the high incidence of cancer that accompanies the use of CsA in organ transplant patients (50). Hyperactivation of protein tyrosine kinases, including Itk, during clinical use of PPIase inhibitors may contribute to unregulated cellular proliferation and ultimately formation of malignancies in immunosuppressed patients.…”

Characterization of a Gene Encoding Two Isoforms of a Mitochondrial Protein Up-regulated by Cyclosporin A in Activated T Cells

“…Different reports suggest that therapy with immunosuppressors can specifically stimulate the transcription of genes that may contribute to the onset of complications arising from therapy. In par-ticular, CSA increases transcription of the transforming growth factor ␤ gene, suggesting that CSA may induce tumors in part due to overexpression of this immunosuppressive cytokine (13,14). The finding that CSA up-regulates gene expression in cells from different tissues irrespective of their activation state suggests that calcineurin may be the ubiquitous target, which could then affect gene expression either negatively or positively.…”