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

Oncogene volume 35, pages 5132–5143 (2016)Cite this article

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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 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.

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Acknowledgements

This work was supported by the Italian Association for Cancer Research (AIRC) and the Fondazione Umberto Veronesi (FUV) grants awarded to MG. We thank Michael Forte and Paolo Bernardi for helpful discussion and for providing CypDKO mice, Mariano Barbacid for K-Ras/RERT mice, Jacob Tropmair for MEK-1 mutants and Novartis (Basel-Switzerland) for Deb025.

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  1. Department of Experimental Oncology, European Institute of Oncology, Milan, Italy

    A Bigi, E Beltrami, M Trinei, M Stendardo, P G Pelicci & M Giorgio

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Correspondence to M Giorgio.

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Bigi, A., Beltrami, E., Trinei, M. et al. Cyclophilin D counteracts P53-mediated growth arrest and promotes Ras tumorigenesis. Oncogene 35, 5132–5143 (2016). https://doi.org/10.1038/onc.2016.42

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