title: AKT1 and MYC induce distinctive metabolic fingerprints in human prostate cancer.
abstract: Cancer cells may overcome growth factor dependence by deregulating oncogenic and/or tumor-suppressor pathways that affect their metabolism, or by activating metabolic pathways de novo with targeted mutations in critical metabolic enzymes. It is unknown whether human prostate tumors develop a similar metabolic response to different oncogenic drivers or a particular oncogenic event results in its own metabolic reprogramming. Akt and Myc are arguably the most prevalent driving oncogenes in prostate cancer. Mass spectrometry-based metabolite profiling was performed on immortalized human prostate epithelial cells transformed by AKT1 or MYC, transgenic mice driven by the same oncogenes under the control of a prostate-specific promoter, and human prostate specimens characterized for the expression and activation of these oncoproteins. Integrative analysis of these metabolomic datasets revealed that AKT1 activation was associated with accumulation of aerobic glycolysis metabolites, whereas MYC overexpression was associated with dysregulated lipid metabolism. Selected metabolites that differentially accumulated in the MYC-high versus AKT1-high tumors, or in normal versus tumor prostate tissue by untargeted metabolomics, were validated using absolute quantitation assays. Importantly, the AKT1/MYC status was independent of Gleason grade and pathologic staging. Our findings show how prostate tumors undergo a metabolic reprogramming that reflects their molecular phenotypes, with implications for the development of metabolic diagnostics and targeted therapeutics.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Carmen
authors.initials: C
authors.lastname: Priolo
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Saumyadipta
authors.initials: S
authors.lastname: Pyne
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Joshua
authors.initials: J
authors.lastname: Rose
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Erzsébet Ravasz
authors.initials: ER
authors.lastname: Regan
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Zadra
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Photopoulos
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Stefano
authors.initials: S
authors.lastname: Cacciatore
authors.affiliation: Department of Pathology, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Denise
authors.initials: D
authors.lastname: Schultz
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Natalia
authors.initials: N
authors.lastname: Scaglia
authors.affiliation: Metabolon Inc., Durham, North Carolina.
authors.forename: Jonathan
authors.initials: J
authors.lastname: McDunn
authors.affiliation: Department of Pathology, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Angelo M
authors.initials: AM
authors.lastname: De Marzo
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Boston, Massachusetts. Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts. The Broad Institute, Cambridge, Massachusetts. Division of Cancer Studies, King's College London, United Kingdom. massimo_loda@dfci.harvard.edu.
authors.forename: Massimo
authors.initials: M
authors.lastname: Loda
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D053858:Metabolic Networks and Pathways / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D060787:Neoplasm Grading; D009363:Neoplasm Proteins / Q000096:biosynthesis; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; D016271:Proto-Oncogene Proteins c-myc; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt