Abstract B59: Targeting metabolic enzymes in cancer prevention: Mechanistic insight into reciprocal regulation of isoforms of pyruvate kinase and isocitrate dehydrogenase in the early stage of cancer development
Authors: Robbins Delira F. , VanRemmen Holly , Richardson Arlan , Wang David B. , Witt Stephan N. , Klein Ronald L. , Zhao Yunfeng , Wittwer Jennifer A. , Wang Fei , Codarin Sarah , Shen Xinggui , Kevil Christopher G. , Circu Magdalena L. , Aw Tak Yee , Huang Ting Ting 
Published: June 2012

Cancer cells distinguish themselves from normal cells in multiple ways. One such distinction is that cancer cells predominantly produce energy by a high rate of glycolysis followed by lactic acid fermentation even in the presence of oxygen, known as the “Warburg Effect”. Although glycolysis is inefficient to produce ATP compared with oxidative phosphorylation, metabolic intermediates produced during glycolysis may provide building blocks for cancer cells. Associated with this metabolic switch is up- or down-regulation of important metabolic enzymes, such as the M1 and M2 isoforms of pyruvate kinase (PKM1; PKM2) and isocitrate dehydrogenase 1 and 2 (IDH1; IDH2).

PKM2 is highly expressed and critical for proliferation of tumor cells. Our initial studies showed that both UV irradiation and tumor promoters altered cellular metabolism via upregulating the activity and expression levels of PKM2 and downregulating PKM1. However, this M1/M2 shift has not been reported in early stage of cancer development.

IDH1, a cytosolic enzyme which converts isocitrate to alpha-ketoglutarate, was recently discovered to be mutated in human brain cancer and leukemia. Interestingly, wild-type IDH1 produces alpha-ketoglutarate; however, mutant IDH1 generates 2-hydroxyglutarate, a known “oncometabolite.” We have found that decreased expression and activity levels of IDH1, not IDH2 were seen both in vitro in the tumor promotable JB6 P+ cell model and in vivo using mouse skin epidermal tissues, following UV and 12–0-tetradecanoylphorbol 13-acetate (TPA) treatment. More importantly, knockdown of IDH1 enhanced whereas overexpression of IDH1 suppressed cell transformation induced by tumor promoter TPA.

During tumorigenesis, oncogenic activation can also generate oxidative stress. Since metabolism is the major source for ROS (reactive oxygen species) production, metabolic changes often observed in cancer cells may also be regulated by oxidative stress. Our initial studies revealed that PKM2 was upregulated and IDH1 downregulated in promotable mouse skin epidermal JB6 P+ cells, not in non-promotable JB6 P-cells. We have observed in previous studies that MnSOD expression/activity is lower in P+ cells, compared to P-cells, thus providing evidence that PKM2 activation and IDH1 inactivation may be regulated by oxidative stress. Lastly, overexpression of manganese superoxide dismutase (MnSOD) suppressed tumor promoter-induced PKM2 activation and decreased IDH1 expression. These results suggest that oxidative stress may contribute to PKM2 activation and IDH1 inactivation during early stage tumor promotion, suggesting mediation with MnSOD, a mitochondrial antioxidant enzyme, may play a cancer preventative role in regulating cellular metabolism.

Citation Information: Cancer Prev Res 2011;4(10 Suppl):B59.