American Association for Cancer Research
00085472can201998-sup-245128_2_supp_6648150_qp71pb.avi (31.14 MB)

Movie S1 from Endocytosis-Mediated Replenishment of Amino Acids Favors Cancer Cell Proliferation and Survival in Chromophobe Renal Cell Carcinoma

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posted on 2023-03-31, 04:06 authored by Yi Xiao, Anja Rabien, René Buschow, Vyacheslav Amtislavskiy, Jonas Busch, Ergin Kilic, Sonia L. Villegas, Bernd Timmermann, Moritz Schütte, Thorsten Mielke, Marie-Laure Yaspo, Klaus Jung, David Meierhofer

Live-cell fluorescence imaging showed that the DQ-Red BSA accumulated in UOK276 cells over time, providing evidence that macropinocytosis is an established process in chRCC cells to uptake macromolecules as nutrient source.



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 and papillary RCC. 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 phospholipase C gamma 2 (PLCG2)/inositol 1,4,5-trisphosphate (IP3)/Ca2+/protein kinase C (PKC) pathway significantly impaired the activation of endocytosis for amino acid 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 patients with chRCC. This study reveals macropinocytosis as an important process utilized by chRCC to gain extracellular nutrients in a p53-independent manner.

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