Multi-omics & pathway analysis identify potential roles for tumor N-acetyl aspartate accumulation in murine models of castration-resistant prostate cancer

被引:5
作者
Salji, Mark J. [1 ,2 ]
Blomme, Arnaud [1 ,2 ]
Dabritz, J. Henry M. [1 ,2 ]
Repiscak, Peter [1 ,2 ]
Lilla, Sergio [1 ,2 ]
Patel, Rachana [1 ,2 ]
Sumpton, David [1 ,2 ]
van den Broek, Niels J. F. [1 ,2 ]
Daly, Ronan [1 ,2 ]
Zanivan, Sara [1 ,2 ]
Leung, Hing Y. [1 ,2 ]
机构
[1] Univ Glasgow, Coll Med Vet & Life Sci, Inst Canc Sci, Glasgow G61 1QH, Lanark, Scotland
[2] CRUK Beatson Inst, Glasgow G61 1BD, Lanark, Scotland
基金
英国医学研究理事会;
关键词
COMPUTATIONAL PLATFORM; METABOLISM; GLUTAMATE; ACETYLASPARTATE;
D O I
10.1016/j.isci.2022.104056
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Castration-resistant prostate cancer (CRPC) is incurable and remains a significant worldwide challenge (Oakes and Papa, 2015). Matched untargeted multi-level omic datasets may reveal biological changes driving CRPC, identifying novel biomarkers and/or therapeutic targets. Untargeted RNA sequencing, proteomics, and metabolomics were performed on xenografts derived from three independent sets of hormone naive and matched CRPC human cell line models of local, lymph node, and bone metastasis grown as murine orthografts. Collectively, we tested the feasibility of muti-omics analysis on models of CRPC in revealing pathways of interest for future validation investigation. Untargeted metabolomics revealed NAA and NAA Gcommonly accumulating in CRPC across three independentmodels and proteomics showed upregulation of related enzymes, namely N-acetylated alpha-linked acidic dipeptidases (FOLH1/NAALADL2). Based on pathway analysis integrating multiple omic levels, we hypothesize that increased NAA in CRPC may be due to upregulation of NAAG hydrolysis via NAALADLases providing a pool of acetyl Co-A for upregulated sphingolipid metabolism and a pool of glutamate and aspartate for nucleotide synthesis during tumor growth.
引用
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页数:17
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