Pyruvate kinase isozyme M2 and glutaminase might be promising molecular targets for the treatment of gastric cancer

Abstract

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 four parent cell lines were used. Reverse transcription–PCR was used to evaluate the mRNA expression levels of the following metabolism‐related enzymes: pyruvate kinase isozyme M2 (PKM2), glutaminase (GLS), enolase 1 (ENO1), glucose‐6‐phosphate dehydrogenase (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 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 using shikonin and BPTES inhibited the proliferation of all hypoxia‐resistant cancer cells more than that by either agent alone. 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 could be therapeutically promising for the treatment of gastric cancer.

<p>Metabolic reprogramming results in abnormal glycolysis in gastric cancer: a review</p>

“…Tumor cells generally express high levels of PKM2 and low levels of PKM1, thereby promoting glycoly-sis and inhibiting mitochondrial oxidative phosphorylation 16. When PKM2 was knocked out in GC cells, the PI3K/AKT/ mTOR pathway and autophagy were inhibited, thereby leading to a decrease in the proliferation and invasive phenotype of GC cells 17,18. PKM2 can also translocate to the nucleus and promote transcription of HIF-1α and Bcl-xl to further enhance glycolysis 19.…”

SDF1&alpha;/CXCR4 axis may be associated with the malignant progression of gastric cancer in the hypoxic tumor microenvironment

“…Recent studies have demonstrated that SDF1α is upregulated in fibroblasts to fulfill its role in cell protection against hypoxia (4,32). These results suggested that the heterogeneous hypoxic environment in cancer may be one of the reasons for cancer heterogenicity, which is associated with tumor resistance for various types of therapy (15,47,48). SDF1α may serve as a protective factor to promote cell repair following hypoxic injury via its main receptor, CXCR4 (49).…”

“…Various types of solid tumors, including GC have a heterogeneously hypoxic environment which is currently thought to be associated with aggressive tumor phenotypes (15)(16)(17)(18)(19). Clinical and experimental data on GC also provide evidence of an association between the hypoxic environment and a poor prognosis (16,18).…”

Inhibitory effects of iron depletion plus eribulin on the breast cancer microenvironment

“…After 24 h, the cells were harvested and washed twice with phosphate-buffered saline and stained using the CycleTEST TM PLUS DNA Reagent kit according to the manufacturer's instructions (Becton Dickinson Biosciences, CA-San Jose, USA). Staining intensity was quanti ed using a BD LSR II ow cytometer with FACSDiva TM software (Becton Dickinson Biosciences) [17,18].…”