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Series GSE60422 Query DataSets for GSE60422
Status Public on Jul 01, 2016
Title Synthetic cystine addiction via programmed necrosis in VHL-deficient renal cell carcinoma
Organism Homo sapiens
Experiment type Expression profiling by array
Summary Altered metabolism is an important part of malignant transformation of tumor cells. Oncogenic transformation may reprogram tumor metabolism and render tumor cells addicted to extracellular nutrients. Such nutrient addictions associated with oncogenic mutations may offer therapeutic opportunities; however, it remains difficult to predict these nutrient addictions. Here, we performed a nutrigenetic screen to determine the phenotypes of isogenic pairs of clear-cell renal cancer cells (ccRCC) with or without VHL upon the deprivation of individual amino acids. We identified that cystine deprivation triggered rapid programmed necrosis in VHL-deficient RCC, but not in their VHL-restored counterparts. Similar cystine addiction was also observed in VHL-deficient primary RCC tumors cells. Blockage of cystine uptake significantly delayed xenograft growth of ccRCC. Importantly, cystine deprivation triggered similar metabolic changes regardless of VHL status. Therefore, metabolic differences due to cystine deprivation are not different enough to readily explain the distinct fate of life vs. death in VHL-deficient and restored cell.. Instead, we found that increased levels of TNFα associated with VHL loss in the VHL-deficient RCC force them to rely on intact RIPK1 to inhibit apoptosis. However, this pre-existing elevated TNFα in the VHL-deficient ccRCC renders these cells susceptible to the necrosis signaling triggered by cystine deprivation. In addition, we identified that cystine-deprived necrosis in VHL-deficient RCC depends on reciprocal amplification of the Src-p38-Noxa signaling and TNFα-RIP1/3-MLKL necrosis pathways that culminate in MLKL oligomerization and programmed necrosis. Together, our data reveal that the contextual cystine-addictions in VHL-deficient ccRCC is dependent on activating pre-existing oncogenic pathways to trigger programmed necrosis.
Overall design RNA was extracted by RNAeasy kits (Qiagen) from the RCC4 Vec and VHL-reconstituted cells which were exposed to the control full DMEM or cystine deprived DMEM media for 6 hours (three replicates in each condition).
Contributor(s) Tang X, Chi J
Citation(s) 26833124
Submission date Aug 14, 2014
Last update date Dec 06, 2018
Contact name Xiaohu Tang
Organization name Duke University
Department Department of Molecular Genetics and Microbiology
Street address CIEMAS Rm 2133, 101 Science Dr.
City Durham
State/province NC
ZIP/Postal code 27708
Country USA
Platforms (1)
GPL571 [HG-U133A_2] Affymetrix Human Genome U133A 2.0 Array
Samples (12)
GSM1479396 RCC4-Vec_Control_6h-rep1
GSM1479397 RCC4-Vec_Control_6h-rep2
GSM1479398 RCC4-Vec_Control_6h-rep3
BioProject PRJNA258218

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Supplementary file Size Download File type/resource
GSE60422_RAW.tar 24.2 Mb (http)(custom) TAR (of CEL)
Processed data included within Sample table

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