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 vs. AKT1-high tumors, or in normal vs. 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 which reflects their molecular phenotypes, with implications for the development of metabolic diagnostics and targeted therapeutics.

MYC and metabolism on the path to cancer

“…Overexpression of Myc in human prostate epithelial cells upregulates FASN transcriptionally and translationally [92]. Metabolomic analysis also shows enrichment of phospholipid and lipid precursor citrate in the Myc overexpressing cells, suggesting high levels of Myc are linked to elevated fatty acid synthesis [92].…”

“…Overexpression of Myc in human prostate epithelial cells upregulates FASN transcriptionally and translationally [92]. Metabolomic analysis also shows enrichment of phospholipid and lipid precursor citrate in the Myc overexpressing cells, suggesting high levels of Myc are linked to elevated fatty acid synthesis [92]. Direct evidence that c-Myc drives de novo fatty-acid biosynthesis includes use of 13 C-labeled glucose, which reveals a near doubling in the fraction of palmitate isotopomers in Myc-expressing rat fibroblasts (11%) compared to Myc-null cells (6%) [93].…”

“…Notably, by activating multiple metabolic pathways, Myc-overexpressing cells are more resistant to individual metabolic perturbations [100]. Furthermore, metabolomic analyses in mouse and human prostate cancer tissue expressing high levels of Akt or Myc have shown that, while high level of Akt is associated with accumulation of glycolytic metabolites, Myc overexpression prompts accumulation of metabolites downstream of glutamine and lipid metabolism [92]. Although further work is necessary to address the effectiveness of anti-metabolic therapy for cancer cells, differentially targeting according to the particular metabolic dependencies arising from the genetic of each cancer appears important.…”

Integration of Metabolomics and Transcriptomics Reveals Major Metabolic Pathways and Potential Biomarker Involved in Prostate Cancer

“…However, its integration with other "-omic" studies may provide a more in-depth understanding of intratumor processes (13,14). Metabolic profiling or metabolomics provides data-rich information of metabolic alterations that reflect genetic, epigenetic, and environmental factors influencing cellular physiology (15). Integration of transcriptomics and metabolomics may yield further insight into tumor pathogenesis than either approach alone.…”

Challenging Roadblocks to Cancer Cure

“…Simultaneous targeting of selected metabolic enzymes/pathways and driving oncogenes may represent an effective therapeutic approach (11). More specifically, targeting both cell cycleproliferative checkpoints and the tumor viability-specific metabolic support system could be an effective therapeutic strategy in cancers with high proliferative rates.…”