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Mechanisms of regulation of PFKFB expression in pancreatic and gastric cancer cells

World Journal of Gastroenterology 2014年第38期20卷 13705-13717页

作者： Oleksandr H Minchenko Katsuya Tsuchihara Dmytro O Minchenko Andreas Bikfalvi Hiroyasu Esumi Department of Molecular Biology Palladin Institute of Biochemistry Department of Innovative Oncology National Cancer Center Department of Pediatrics Bogomolets National Medical University INSERM U1029 Molecular Angiogenesis and Cancer Microenvironment Laboratory University Bordeaux I

Enzymes 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 and -4 (PFKFB-3 and PFKFB-4) play a significant role in the regulation of glycolysis in cancer cells as well as its proliferation and survival. The expression of these mRNAs is increased in malignant tumors and strongly induced in different cancer cell lines by hypoxia inducible factor (HIF) through active HIF binding sites in promoter region of PFKFB-4 and PFKFB-3 genes. Moreover, the expression and hypoxia responsibility of PFKFB-4 and PFKFB-3 was also shown for pancreatic (Panc1, PSN-1, and MIA PaCa-2) as well as gastric (MKN45 and NUGC3) cancer cells. At the same time, their basal expression level and hypoxia responsiveness vary in the different cells studied: the highest level of PFKFB-4 protein expression was found in NUGC3 gastric cancer cell line and lowest in Panc1 cells, with a stronger response to hypoxia in the pancreatic cancer cell line. Overexpression of different PFKFB in pancreatic and gastric cancer cells under hypoxic condition is correlated with enhanced expression of vascular endothelial growth factor (VEGF) and Glut1 mRNA as well as with increased level of HIF-1α protein. Increased expression of different PFKFB genes was also demonstrated in gastric, lung, breast, and colon cancers as compared to corresponding non-malignant tissue counterparts from the same patients, being more robust in the breast and lung tumors. Moreover, induction of PFKFB-4 mRNA expression in the breast and lung cancers is stronger than PFKFB-3 mRNA. The levels of both PFKFB-4 and PFKFB-3 proteins in non-malignant gastric and colon tissues were more pronounced than in the non-malignant breast and lung tissues. It is interesting to note that Panc1 and PSN-1 cells transfected with dominant/negative PFKFB-3 (dnPFKFB-3) showed a lower level of endogenous PFKFB-3, PFKFB-4, and VEGF mRNA expressions as well as a decreased proliferation rate of these cells. Moreover, a similar effect had dnPFKFB-4. In conclusi

关键词： 6-phosphofructo-2-kinase/fructose-2 6-bisphosphatase-3 6-phosphofructo-2-kinase/fructose-2 6-bisphosphatase-4 Hypoxia Hypoxia inducible factor Panc1 PST-1 MKN45 NUGC3 Gastric cancer Lung cancer

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