Endocytosis-mediated replenishment of amino acids favors cancer cell proliferation and survival in chromophobe renal cell carcinoma.

Chromophobe renal cell carcinoma (chRCC) accounts for approximately 5% of all renal cancers and around 30% of chRCC cases have mutations in TP53. ChRCC is poorly supported by microvessels and has markably lower glucose uptake than clear cell RCC (ccRCC) and papillary RCC (pRCC). Currently, the metabolic status and mechanisms by which this tumor adapts to nutrient-poor microenvironments remain to be investigated. In this study, we performed proteome and metabolome profiling of chRCC tumors and adjacent kidney tissues and identified major metabolic alterations in chRCC tumors, including the classical Warburg effect, the downregulation of gluconeogenesis and amino acid metabolism, and the upregulation of protein degradation and endocytosis. ChRCC cells depended on extracellular macromolecules as an amino acid source by activating endocytosis to sustain cell proliferation and survival. Inhibition of the PLCG2/IP3/Ca2+/PKC pathway significantly impaired the activation of endocytosis for amino acids uptakes into chRCC cells. In chRCC, whole-exome sequencing revealed that TP53 mutations were not related to expression of PLCG2 and activation of endocytosis. Our study provides novel perspectives on metabolic rewiring in chRCC and identifies the PLCG2/IP3/Ca2+/PKC axis as a potential therapeutic target in chRCC patients.

Cancer research. 2020 Oct 28 [Epub ahead of print]

Yi Xiao, Anja Rabien, René Buschow, Vyacheslav Amstislavskiy, Jonas Busch, Ergin Kilic, Sonia L Villegas, Bernd Timmermann, Moritz Schütte, Thorsten Mielke, Marie-Laure Yaspo, Klaus Jung, David Meierhofer

Mass Spectrometry Facility, Max Planck Institute for Molecular Genetics., Urology, Charité - Universitätsmedizin Berlin., Microscopy and Cryo-Electron Microscopy, Max Planck Institute for Molecular Genetics., Otto Warburg Laboratory Gene Regulation and Systems Biology of Cancer, Max Planck Institute for Molecular Genetics., Department of Urology, Charité Universitatsmedizin Berlin., Pathologie Leverkusen., Pathology, Institute of Pathology, Charité - Universitätsmedizin Berlin., Next generation sequencing group, Vertebrate Genomics, Max Planck Institute for Molecular Genetics., Data analysis, Alacris Theranostics GmbH., Microscopy and Cryo-Electronmicroscopy Service Group, Max Planck Institute for Molecular Genetics, Berlin, Germany., Otto Warburg Laboratory, Max Planck Institute for Molecular Genetics., Res Div, Dept Urol,, Humboldt University., Mass Spectrometry Facility, Max Planck Institute for Molecular Genetics .