title: Cystine Deprivation Triggers Programmed Necrosis in VHL-Deficient Renal Cell Carcinomas.
abstract: Oncogenic transformation may reprogram tumor metabolism and render cancer cells addicted to extracellular nutrients. Deprivation of these nutrients may therefore represent a therapeutic opportunity, but predicting which nutrients cancer cells become addicted remains difficult. 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 found that cystine deprivation triggered rapid programmed necrosis in VHL-deficient cell lines and primary ccRCC tumor cells, but not in VHL-restored counterparts. Blocking cystine uptake significantly delayed xenograft growth of ccRCC. Importantly, cystine deprivation triggered similar metabolic changes regardless of VHL status, suggesting that metabolic responses alone are not sufficient to explain the observed distinct fates of VHL-deficient and restored cells. Instead, we found that increased levels of TNFα associated with VHL loss forced VHL-deficient cells to rely on intact RIPK1 to inhibit apoptosis. However, the preexisting elevation in TNFα expression rendered VHL-deficient cells susceptible to necrosis triggered by cystine deprivation. We further determined that reciprocal amplification of the Src-p38 (MAPK14)-Noxa (PMAIP1) signaling and TNFα-RIP1/3 (RIPK1/RIPK3)-MLKL necrosis pathways potentiated cystine-deprived necrosis. Together, our findings reveal that cystine deprivation in VHL-deficient RCCs presents an attractive therapeutic opportunity that may bypass the apoptosis-evading mechanisms characteristic of drug-resistant tumor cells. Cancer Res; 76(7); 1892-903. ©2016 AACR.
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University, Durham, North Carolina. Center for Genomic and Computational Biology Duke University, Durham, North Carolina.
authors.forename: Xiaohu
authors.initials: X
authors.lastname: Tang
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University, Durham, North Carolina. Center for Genomic and Computational Biology Duke University, Durham, North Carolina.
authors.forename: Jianli
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University, Durham, North Carolina. Center for Genomic and Computational Biology Duke University, Durham, North Carolina.
authors.forename: Chien-Kuang
authors.initials: CK
authors.lastname: Ding
authors.affiliation: Center for Genomic and Computational Biology Duke University, Durham, North Carolina. Department of Medicine, Duke University, Durham, North Carolina.
authors.forename: Min
authors.initials: M
authors.lastname: Lu
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University, Durham, North Carolina. Center for Genomic and Computational Biology Duke University, Durham, North Carolina.
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Keenan
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University, Durham, North Carolina. Center for Genomic and Computational Biology Duke University, Durham, North Carolina.
authors.forename: Chao-Chieh
authors.initials: CC
authors.lastname: Lin
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University, Durham, North Carolina. Center for Genomic and Computational Biology Duke University, Durham, North Carolina.
authors.forename: Chih-An
authors.initials: CA
authors.lastname: Lin
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University, Durham, North Carolina. Center for Genomic and Computational Biology Duke University, Durham, North Carolina.
authors.forename: Charles C
authors.initials: CC
authors.lastname: Wang
authors.affiliation: Department of Medicine, Duke University, Durham, North Carolina.
authors.forename: Daniel
authors.initials: D
authors.lastname: George
authors.affiliation: Center for Genomic and Computational Biology Duke University, Durham, North Carolina. Department of Medicine, Duke University, Durham, North Carolina.
authors.forename: David S
authors.initials: DS
authors.lastname: Hsu
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University, Durham, North Carolina. Center for Genomic and Computational Biology Duke University, Durham, North Carolina. jentsan.chi@duke.edu.
authors.forename: Jen-Tsan
authors.initials: JT
authors.lastname: Chi
mesh_terms: D000818:Animals; D002292:Carcinoma, Renal Cell / Q000378:metabolism*; D045744:Cell Line, Tumor; D003553:Cystine / Q000378:metabolism*; D006801:Humans; D055432:Metabolomics; D051379:Mice; D016688:Mice, Inbred NOD; D009336:Necrosis; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics*
chemical_list: D003553:Cystine; D051794:Von Hippel-Lindau Tumor Suppressor Protein
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