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

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/Ca 2+ /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/Ca 2+ /PKC axis as a potential therapeutic target in chRCC patients. Statement of Significance: This work reveals macropinocytosis as an important process utilized by chRCC to gain extracellular nutrients in a p53-independent manner. Research.

Amino acid starvation‐induced LDLR trafficking accelerates lipoprotein endocytosis and LDL clearance

“…In cells where endogenous cholesterol synthesis is blocked, the cells rely on endocytosis of exogenous LDL as the source of cholesterol for maintaining membrane integrity (Goldstein & Brown, 2009 ). Supporting our hypothesis, emerging evidence shows that certain tumor cells can survive the nutrient‐poor microenvironment by activating endocytosis of extracellular macromolecules as the source of amino acids (Xiao et al , 2020 ). Moreover, it is known that, at least in hepatocytes, the protein components of internalized lipoprotein molecules are degraded by the lysosome system, releasing free amino acids (Heeren & Beisiegel, 2001 ).…”

Single-cell Transcriptomic Architecture Unraveling the Complexity of Tumor Heterogeneity in Distal Cholangiocarcinoma

“…Both genes have been reported to show recurrent mutations in cancer and are associated with a poor prognosis. 20 , 21 Next, we compared the transcriptomic data between all malignant cells and normal epithelial cells, identifying 212 up-regulated genes in malignant and 70 relatively high-expressed genes in normal tissue ( Figure 3 , G ). Kyoto Encyclopedia of Genes and Genomes analysis demonstrated that those highly expressed genes in malignancy were enriched in, for instance, cell junction, ErbB and Notch signaling pathways ( Figure 3 , H ).…”

Hypersensitivity to ferroptosis in chromophobe RCC is mediated by a glutathione metabolic dependency and cystine import via solute carrier family 7 member 11

“…We and others have demonstrated that glutathione levels are strikingly elevated in ChRCC, to levels that are 50- to 100-fold higher than matched normal kidney. These high levels of glutathione are accompanied by extremely low expression of GGT1, which degrades extracellular GSH and is 100-fold lower in ChRCC compared with normal kidney at the messenger RNA (mRNA) level ( 7 , 14 ) and 70-fold lower at the protein level ( 28 ). Exogenous GGT1 was expressed at higher levels than normal kidney to test gain-of-function effects on ChRCC tumorigenesis ( Fig.…”