title: Cyclophilin D counteracts P53-mediated growth arrest and promotes Ras tumorigenesis.
abstract: 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 p21(WAF1/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.
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Bigi
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Beltrami
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Trinei
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Stendardo
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: P G
authors.initials: PG
authors.lastname: Pelicci
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Giorgio
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology; D063646:Carcinogenesis / Q000235:genetics; D002453:Cell Cycle / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics*; D041681:NIH 3T3 Cells; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays; D054462:p21-Activated Kinases / Q000235:genetics*; D018631:ras Proteins / Q000235:genetics
chemical_list: D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins; D019908:Proto-Oncogene Proteins c-raf; D018719:Erb-b2 Receptor Tyrosine Kinases; D016159:Tumor Suppressor Protein p53; D054462:p21-Activated Kinases; D018631:ras Proteins; C000631446:PPIF protein, mouse; C495901:TP53 protein, human; C508053:ERBB2 protein, human; C515905:Pak1 protein, mouse