Cancer cells preferentially perform aerobic glycolysis, metabolizing glucose into lactate despite the presence of oxygen. This process allows the cell to produce macromolecules essential for fast cell growth and division, while still generating sufficient ATP. Our lab has found that in mouse fibroblasts lacking the tumor suppressor p27kip1, low glucose conditions activate a switch to amino acids as a carbon source.  Thus, deregulating p27 may provide a growth advantage during early tumor development by optimizing nutrient uptake from available options. Once angiogenesis occurs, p27 could be upregulated to activate the metabolic switch to readily use available glucose. For this study, we used matched immortalized mouse embryo fibroblasts without p27 (-/-) and with p27 (+/+ wild-type control cell lines). Metabolic inhibitors (2-deoxy glucose and rotenone) were employed to show that cells lacking p27 were able to switch between glucose and amino acid metabolism depending on conditions, while the wild-type cells could not. These observations suggest that a combination of metabolic inhibitors might be able to specifically target cancer cells lacking p27. Rotenone, however, is poisonous, so in this project we screened for novel compounds that would synergize with 2-deoxyglucose to specifically target p27 (-/-) cells. Effects on ATP levels were measured using CellTiterGlo<sup>TM</sup>, and wild type cells containing p27 served as the control. Results from these studies provide further insight into ongoing attempts to specifically target aggressive cancers with deregulated p27.

Drug screening for metabolic inhibitors in cells lacking the tumor suppressor p27kip1

2019 Spring National Meeting

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