Minchenko Oleksandr H, Tsuchihara Katsuya, Minchenko Dmytro O, Bikfalvi Andreas, Esumi Hiroyasu
Oleksandr H Minchenko, Dmytro O Minchenko, Department of Molecular Biology, Palladin Institute of Biochemistry, Kiev 01601, Ukraine.
World J Gastroenterol. 2014 Oct 14;20(38):13705-17. doi: 10.3748/wjg.v20.i38.13705.
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 conclusion, there is strong evidence that PFKFB-4 and PFKFB-3 isoenzymes are induced under hypoxia in pancreatic and other cancer cell lines, are overexpressed in gastric, colon, lung, and breast malignant tumors and undergo changes in their metabolism that contribute to the proliferation and survival of cancer cells. Thus, targeting these PFKFB may therefore present new therapeutic opportunities.
6-磷酸果糖-2-激酶/果糖-2,6-二磷酸酶-3和-4（PFKFB-3和PFKFB-4）在癌细胞糖酵解及其增殖和存活的调节中发挥着重要作用。这些mRNA在恶性肿瘤中的表达增加，并且在不同癌细胞系中，缺氧诱导因子（HIF）通过PFKFB-4和PFKFB-3基因启动子区域的活性HIF结合位点强烈诱导其表达。此外，还显示了PFKFB-4和PFKFB-3在胰腺（Panc1、PSN-1和MIA PaCa-2）以及胃癌细胞（MKN45和NUGC3）中的表达及对缺氧的反应性。同时，它们在不同研究细胞中的基础表达水平和缺氧反应性有所不同：在NUGC3胃癌细胞系中发现PFKFB-4蛋白表达水平最高，在Panc1细胞中最低，并且胰腺癌细胞系对缺氧的反应更强。在缺氧条件下，胰腺和胃癌细胞中不同PFKFB的过表达与血管内皮生长因子（VEGF）和Glut1 mRNA的表达增强以及HIF-1α蛋白水平升高相关。与同一患者相应的非恶性组织相比，在胃癌、肺癌、乳腺癌和结肠癌中也证实了不同PFKFB基因的表达增加，在乳腺癌和肺癌肿瘤中更为明显。此外，乳腺癌和肺癌中PFKFB-4 mRNA表达的诱导强于PFKFB-3 mRNA。非恶性胃和结肠组织中PFKFB-4和PFKFB-3蛋白的水平比非恶性乳腺和肺组织中更明显。有趣的是，用显性/阴性PFKFB-3（dnPFKFB-3）转染的Panc1和PSN-1细胞显示内源性PFKFB-3、PFKFB-4和VEGF mRNA表达水平较低，并且这些细胞的增殖率降低。此外，dnPFKFB-4也有类似作用。总之，有强有力的证据表明，PFKFB-4和PFKFB-3同工酶在胰腺和其他癌细胞系中在缺氧条件下被诱导，在胃癌、结肠癌、肺癌和乳腺癌恶性肿瘤中过表达，并且其代谢发生变化，这有助于癌细胞的增殖和存活。因此，靶向这些PFKFB可能会带来新的治疗机会。
