[en] 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 NAAG commonly accumulating in CRPC across three independent models 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.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Salji, Mark J ; Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Bearsden, Glasgow G61 1QH, UK ; CRUK Beatson Institute, Bearsden, Glasgow G61 1BD, UK
Blomme, Arnaud ; Université de Liège - ULiège > Département de pharmacie ; Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Bearsden, Glasgow G61 1QH, UK ; CRUK Beatson Institute, Bearsden, Glasgow G61 1BD, UK
Däbritz, J Henry M; Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Bearsden, Glasgow G61 1QH, UK ; CRUK Beatson Institute, Bearsden, Glasgow G61 1BD, UK
Repiscak, Peter; Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Bearsden, Glasgow G61 1QH, UK ; CRUK Beatson Institute, Bearsden, Glasgow G61 1BD, UK
Lilla, Sergio; Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Bearsden, Glasgow G61 1QH, UK ; CRUK Beatson Institute, Bearsden, Glasgow G61 1BD, UK
Patel, Rachana; Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Bearsden, Glasgow G61 1QH, UK ; CRUK Beatson Institute, Bearsden, Glasgow G61 1BD, UK
Sumpton, David; Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Bearsden, Glasgow G61 1QH, UK ; CRUK Beatson Institute, Bearsden, Glasgow G61 1BD, UK
van den Broek, Niels J F; Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Bearsden, Glasgow G61 1QH, UK ; CRUK Beatson Institute, Bearsden, Glasgow G61 1BD, UK
Daly, Ronan ; Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Bearsden, Glasgow G61 1QH, UK ; CRUK Beatson Institute, Bearsden, Glasgow G61 1BD, UK
Zanivan, Sara; Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Bearsden, Glasgow G61 1QH, UK ; CRUK Beatson Institute, Bearsden, Glasgow G61 1BD, UK
Leung, Hing Y ; Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Bearsden, Glasgow G61 1QH, UK ; CRUK Beatson Institute, Bearsden, Glasgow G61 1BD, UK
Language :
English
Title :
Multi-omics & pathway analysis identify potential roles for tumor N-acetyl aspartate accumulation in murine models of castration-resistant prostate cancer.
We thank the Core Services and Advanced Technologies at the CRUK Beatson Institute, particularly the Metabolomics, Proteomics, RNA sequencing and Bioinformatics units. This work was supported by the Medical Research Council Clinical Research Training Fellowship awarded to MS ( MR/L017997/1 ) and CRUK Beatson Institute core funding ( C596/A31287 ) and CRUK core group awarded to HYL ( A15151 ) and SZ ( A29800 ).We thank the Core Services and Advanced Technologies at the CRUK Beatson Institute, particularly the Metabolomics, Proteomics, RNA sequencing and Bioinformatics units. This work was supported by the Medical Research Council Clinical Research Training Fellowship awarded to MS (MR/L017997/1) and CRUK Beatson Institute core funding (C596/A31287) and CRUK core group awarded to HYL (A15151) and SZ (A29800). MJS, AB, and HYL designed the study. MJS, HMD, SL, RP, DS, and NJFB performed the experiments. MJS, AB, HMD, PR, SL, DS, NJFB, SZ, and RD analyzed the data. MJS, AB, HMD, RD, SZ, and HYL interpreted the data. MJS and HYL wrote the manuscript and all authors reviewed the final manuscript. The authors declare no competing interests.
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