Mass Spectrometry-Based Metabolic Fingerprinting Contributes to Unveil the Role of RSUME in Renal Cell Carcinoma Cell Metabolism

MARTINEFSKI, MANUELA R.; ELGUERO, BELÉN; KNOTT, MARÍA ELENA; GONILSKI, DAVID; TEDESCO, LUCAS; GUREVICH MESSINA, JUAN M.; POLLAK, CORA; ARZT, EDUARDO; MONGE, MARÍA EUGENIA

JOURNAL OF PROTEOME RESEARCH

AMER CHEMICAL SOC

Año: 2021 vol. 20 p. 786 - 803

1535-3893

Clear cell renal cell carcinoma (ccRCC) is a heterogeneous disease with 50-80% patients exhibiting mutations in the von Hippel-Lindau (VHL) gene. RSUME (RWD domain-containing protein SUMO enhancer) acts as a negative regulator of VHL function in normoxia. A discovery-based metabolomics approach was developed by means of ultraperformance liquid chromatography coupled to quadrupole-time-of-flight mass spectrometry (UPLC-QTOF-MS) for fingerprinting the endometabolome of human ccRCC cell lines 786-O and three other transformed cell systems (n=102) with different expression of RSUME and VHL. Cross-validated orthogonal projection to latent structures-discriminant analysis models were built on positive, negative and combined positive and negative ion mode MS datasets. Discriminant feature panels selected by iterative multivariate classification allowed differentiating cells with different expression of RSUME and VHL. Fifteen identified discriminant metabolites with level 1, including glutathione, butyrylcarnitine and acetylcarnitine, contributed to understand the role of RSUME in ccRCC. Altered pathways associated with RSUME expression were validated by biological and bioinformatics analyses. Combined results showed that in absence of VHL, RSUME is involved in downregulation of the antioxidant defense system, whereas in presence of VHL, it acts in re-routing energy related-pathways, negatively modulating the lipid utilization, and positively modulating the fatty acid synthesis, which may promote deposition in droplets.