TY - JOUR
T1 - AKT1 and MYC induce distinctive metabolic fingerprints in human prostate cancer
AU - Priolo, Carmen
AU - Pyne, Saumyadipta
AU - Rose, Joshua
AU - Regan, Erzsébet Ravasz
AU - Zadra, Giorgia
AU - Photopoulos, Cornelia
AU - Cacciatore, Stefano
AU - Schultz, Denise
AU - Scaglia, Natalia
AU - McDunn, Jonathan
AU - De Marzo, Angelo M.
AU - Loda, Massimo
N1 - Publisher Copyright:
©2014 AACR.
PY - 2014/12/15
Y1 - 2014/12/15
N2 - 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 fi ndings show how prostate tumors undergo a metabolic reprogramming that refl ects their molecular phenotypes, with implications for the development of metabolic diagnostics and targeted therapeutics.
AB - 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 fi ndings show how prostate tumors undergo a metabolic reprogramming that refl ects their molecular phenotypes, with implications for the development of metabolic diagnostics and targeted therapeutics.
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U2 - 10.1158/0008-5472.CAN-14-1490
DO - 10.1158/0008-5472.CAN-14-1490
M3 - Article
C2 - 25322691
AN - SCOPUS:84918573255
SN - 0008-5472
VL - 74
SP - 7198
EP - 7204
JO - Cancer Research
JF - Cancer Research
IS - 24
ER -