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 p...