Introduction: The initiation of androgen deprivation therapy (ADT) induces susceptibilities in prostate cancer (PC) cells that make them amenable to synergistic treatments and improved cell killing. However, progression to lethal castrate resistant state still results after the initiation of ADT and highlighting the need for better understanding of PC susceptibilities. Metabolic reprogramming in cancer cells is a hallmark of cancer. We sought to characterize the metabolomics alterations in PC cells induced by initiation of ADT using high-throughput mass spectrometry (MS) and optical metabolic imaging (OMI).
Methods: Hormone-sensitive PC cells (LNCAP) treated with ADT (charcoal stripped media) or control (fetal bovine serum) at 4 and 8 days were collected. Untargeted metabolomics profiling screening for all detectable compounds using validated chromatography/ MS method was used to profile the cells at the two time-points. Chemical Similarity Enrichment Set Analysis (ChemRICH) revealed significantly altered metabolite clusters. Multiphoton fluorescence properties of NADH and FAD were used to calculate the optical redox ratio, which provides a noninvasive, high-resolution, and quantitative tool for monitoring dynamic changes in cellular metabolism.
Results: Using MS data, ADT treated cells displayed 18 and 68 significantly altered metabolites at 4 and 8 days respectively. Subsequent ChemRICH analysis showed 6 metabolite clusters were significantly different (FDR<0.05) between ADT and control. A total of 4 clusters (Sugar Acids, Sugar Alcohol, Hexoses, and Monosaccharides), which serve as the predominant substrates for glycolysis, were increased in ADT treated PC cells. This abundance of glycolysis substrate in combination with OMI (which correlates with glycolytic index) findings of a distinctly decreased reduced redox ratio at 4 and 8 days indicates that glycolysis is in fact diminished in ADT treated cells.
Conclusions: Using multiple metabolomics techniques; this study highlights an ADT-induced shift in hormone sensitive PC cells towards a decrease in reliance on glycolysis as an energy production source/pathway. Further understanding of these adaptations and identification of the primary energy source pathways will have major implications on development of therapies exploiting such shifts. Source of
Funding: Funded by Urology Care Foundation/ AUA Research Scholar Program (T.K.), DOD PCRP PC 150221.