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

MPS-Authors
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Xiao,  Yi
Mass Spectrometry (Head: David Meierhofer), Scientific Service (Head: Christoph Krukenkamp), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Buschow,  Rene
Microscopy and Cryo-Electron Microscopy (Head: Thorsten Mielke), Scientific Service (Head: Christoph Krukenkamp), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Amstislavskiy,  Vyacheslav
Gene Regulation and Systems Biology of Cancer (Marie-Laure Yaspo), Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Timmermann,  Bernd
Sequencing (Head: Bernd Timmermann), Scientific Service (Head: Christoph Krukenkamp), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Mielke,  Thorsten
Microscopy and Cryo-Electron Microscopy (Head: Thorsten Mielke), Scientific Service (Head: Christoph Krukenkamp), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Yaspo,  Marie-Laure
Gene Regulation and Systems Biology of Cancer (Marie-Laure Yaspo), Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Meierhofer,  David
Mass Spectrometry (Head: David Meierhofer), Scientific Service (Head: Christoph Krukenkamp), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Xiao_2020.pdf
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Citation

Xiao, Y., Rabien, A., Buschow, R., Amstislavskiy, V., Busch, J., Kilic, E., et al. (2020). Endocytosis-mediated replenishment of amino acids favors cancer cell proliferation and survival in chromophobe renal cell carcinoma. Cancer research: an official organ of the American Association for Cancer Research, 80, 5491-5501. doi:10.1158/0008-5472.CAN-20-1998.


Cite as: http://hdl.handle.net/21.11116/0000-0007-4F87-9
Abstract
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.