Research Article: Integrated multi-omics characterization reveals a distinctive metabolic signature and the role of NDUFA4L2 in promoting angiogenesis, chemoresistance, and mitochondrial dysfunction in clear cell renal cell carcinoma

Date Published: December 11, 2018

Publisher: Impact Journals

Author(s): Giuseppe Lucarelli, Monica Rutigliano, Fabio Sallustio, Domenico Ribatti, Andrea Giglio, Martina Lepore Signorile, Valentina Grossi, Paola Sanese, Anna Napoli, Eugenio Maiorano, Cristina Bianchi, Roberto A. Perego, Matteo Ferro, Elena Ranieri, Grazia Serino, Lauren N. Bell, Pasquale Ditonno, Cristiano Simone, Michele Battaglia.

http://doi.org/10.18632/aging.101685

Abstract

An altered metabolism is involved in the development of clear cell – renal cell carcinoma (ccRCC), and in this tumor many altered genes play a fundamental role in controlling cell metabolic activities. We delineated a large-scale metabolomic profile of human ccRCC, and integrated it with transcriptomic data to connect the variations in cancer metabolism with gene expression changes. Moreover, to better analyze the specific contribution of metabolic gene alterations potentially associated with tumorigenesis and tumor progression, we evaluated the transcription profile of primary renal tumor cells. Untargeted metabolomic analysis revealed a signature of an increased glucose uptake and utilization in ccRCC. In addition, metabolites related to pentose phosphate pathway were also altered in the tumor samples in association with changes in Krebs cycle intermediates and related metabolites. We identified NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 4-like 2 (NDUFA4L2) as the most highly expressed gene in renal cancer cells and evaluated its role in sustaining angiogenesis, chemoresistance, and mitochondrial dysfunction. Finally, we showed that silencing of NDUFA4L2 affects cell viability, increases mitochondrial mass, and induces ROS generation in hypoxia.

Partial Text

Renal cell carcinoma (RCC) is the twelfth most common cancer in the world, with over 330,000 new cases diagnosed every year. Recent estimates have calculated that in 2018, in the United States 65,340 new cases will be diagnosed and 14,970 patients will die of RCC [1].

Analysis of the ccRCC metabolome and its integration with transcriptomic data revealed significant metabolic alterations in this tumor. In particular, we observed increased levels of metabolites in the upper chain of reactions involving 6-carbon molecules, and a reduction of metabolic intermediates in the lower part of glycolysis, downstream of fructose 6-phosphate. This different distribution of metabolites production between the upper and lower chains of glycolytic reactions suggests that the metabolic flux through this pathway is differentially partitioned. In particular, the sugars generated in the upper part of glycolysis are rerouted to the pentose phosphate pathway, while the triose phosphates produced in the lower part are diverted towards the Krebs cycle or one-carbon metabolism. In this scenario, our results suggest that in ccRCC the mitochondrial bioenergetics and oxidative phosphorylation processes are impaired, and that an increased glucose utilization is promoted through the pentose phosphate pathway. These alterations in glucose metabolism and pentose phosphate pathway were in accordance with our previous findings showing that in ccRCC, oncogenic signaling pathways may promote cancer through rerouting the sugar metabolism [10].

 

Source:

http://doi.org/10.18632/aging.101685

 

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