Abstract 5484: Pyruvate kinase isozymes M2 and glutaminase might be promising molecular targets for the treatment of gastric cancer

Abstract

Abstract Glycolysis is the primary mode of glucose metabolism, not only in normal cells but also in cancer cells. The Warburg effect, known as anaerobic glycolysis even in the presence of ample oxygen, might contribute to tumor development in such hypoxic environments. It has been suggested that some kinds of glucose metabolism-related enzymes—including pyruvate kinase isozyme M2 (PKM2), PKM1, enolase 1 (ENO1), and glucose-6-phosphate dehydrogenase (G6PDH)—might be associated with the anaerobic glycolysis of cancer cells. Glutamine is also associated with the proliferation of cancer cells by an alternate source of biosynthesis from the TCA cycle, namely glutaminolysis. In the present study we evaluated the significance of the enzymes for glycolysis and glutaminolysis in relation to the proliferation of gastric cancer cells in hypoxic environments. The aim of this study was to analyze the significance of glucose metabolism-related enzymes in the proliferation of gastric cancer under hypoxia. Four hypoxia-resistant gastric cancer cell lines and 4 parent cell lines were used. RT-PCR was used to evaluate the mRNA expression levels of the following metabolism-related enzymes: PKM2, GLS, ENO1, G6PDH, and PKM1. The effects of these enzymes on the proliferation of gastric cancer cells were examined using siRNAs, Shikonin as a PKM2 inhibitor, or BPTES as a GLS inhibitor, in vitro and in vivo. Levels of both PKM2 and GLS mRNA were significantly high in all hypoxia-resistant cell lines, compared with those of their parent cells. Knockdown of PKM2 and GLS significantly decreased the proliferation of all of hypoxia-resistant cells. The combination of siPKM2 and siGLS significantly decreased proliferation compared with treatment by siPKM2 or siGLS alone. The knockdown of ENO1, G6PDH, or PKM1 did not decrease the proliferation of all hypoxia-resistant cells. Combination treatment by Shikonin and BPTES inhibited the proliferation of all hypoxia-resistant cancer cells more than that by either one of the two agents. The in vivo study indicated that the tumor size treated by the combination of Shikonin and BPTES was significantly smaller than that of vehicle-treated group. These findings suggested that PKM2 and GLS might play important roles in the proliferation of hypoxic gastric cancer cells. A combination of PKM2 and GLS inhibitors might be therapeutically promising for the treatment of gastric cancer. Citation Format: Masakazu Yashiro, Kishu Kitayama. Pyruvate kinase isozymes M2 and glutaminase might be promising molecular targets for the treatment of gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5484.