Cyclophilin D counteracts P53-mediated growth arrest and promotes Ras tumorigenesis

Mitochondrial alterations induced by oncogenes are known to be crucial for tumorigenesis. Ras oncogene leads to proliferative signals through a Raf-1/MEK/ERK kinase cascade, whose components have been found to be also associated with mitochondria. The mitochondrial pepdidyl-prolyl isomerase cyclophilin D (CypD) is an important regulator of the mitochondrial permeability transition and a key player in mitochondria physiology; however, its role in cancer is still unclear. Using cellular and in vivo mouse models, we demonstrated that CypD protein upregulation induced by oncogenic Ras through the Raf-1/MEK/ERK pathway has a deterministic role in tumor progression. In fact, targeting CypD gene expression clearly affected RasV12-induced transformation, as showed by in vitro data on murine NIH3T3 and human MCF10A mammary epithelial cells. In addition, studies in xenograft and K-Ras lung cancer mouse models demonstrated that genetic deletion or pharmacological suppression of CypD efficiently prevented Ras-dependent tumor formation. Furthermore, Erbb2-mediated breast tumorigenesis was similarly prevented by targeting CypD. From a mechanistic point of view, CypD expression was associated with a reduced induction of p21WAF1/CIP1 and p53 functions, unraveling an antagonistic function of CypD on p21–p53-mediated growth suppression. CypD activity is p53 dependent. Interestingly, a physical association between p53 and CypD was detected in mitochondria of MCF10A cells; furthermore, both in vitro and in vivo studies proved that CypD inhibitor-based treatment was able to efficiently impair this interaction, leading to a tumor formation reduction. All together, these findings indicate that the countering effect of CypD on the p53–p21 pathway participates in oncogene-dependent transformation.