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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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Effect of hypoxia and glutamine or glucose deprivation on the expression of retinoblastoma and retinoblastoma-related genes in ERN1 knockdown glioma u87 cell line

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American Journal of molecular Biology 2012年第1期2卷 21-31页

作者： Dmytro O. Minchenko Leonid L. Karbovskyi Serhii V. Danilovskyi Michel Moenner Oleksandr H. Minchenko Department of molecular Biology Palladin Institute of Biochemistry National Academy of Sciences of Ukraine Kyiv Ukraine Department of molecular Biology Palladin Institute of Biochemistry National Academy of Sciences of Ukraine Kyiv Ukraine inserm u920 molecular Mechanisms of angiogenesis laboratory University Bordeaux 1 Talence France Department of molecular Biology Palladin Institute of Biochemistry National Academy of Sciences of Ukraine Kyiv Ukraine National O.O. Bohomoletz Medical university Kyiv Ukraine inserm u920 molecular Mechanisms of angiogenesis laboratory University Bordeaux 1 Talence France inserm u920 molecular Mechanisms of angiogenesis laboratory University Bordeaux 1 Talence France

The expression of retinoblastoma and several retinoblastoma-related genes was studied in glioma cell line u87 and its subline with knockdown of ERN1 (endoplasmic reticulum—nuclei-1), the main endoplasmic reticulum stress sensing and signaling enzyme. It was shown that a blockade of the ERN1 enzyme function increases the expression levels of retinoblastoma, retinoblastoma-like 1 and most retinoblastoma related genes: EID1, JARID1B, E2F1, E2F3, RBAP48 and CTIP, does not change RNF40 and RBAP46 and decreases KDM5A. We have also demonstrated that hypoxia reduces the expression levels of retinoblastoma, EID1, and E2F1 in ERN1-deficient glioma cells only. At the same time, the expression levels of retinoblastoma-like 1, E2F3, RBAP46, RBAP48 and CTIP decrease, while JARID1B and RBBP2 increase in both types of cells in hypoxic conditions, but the expression is much stronger in cells with suppressed function of ERN1. The expression level of JARID1B and KDM-5A mRNA is also enhanced in glutamine deprivation condition in both tested cell types, moreover, this effect is amplified by the blockade of the ERN1 enzyme function. The expression levels of retinoblastoma, EID1, RBAP48, and E2F3 are decreased in glutamine deprivation condition only in ERN1-deficient glioma cells, but RBL1, CTIP, RBAP46, and E2F1—in both tested cell types with more significant effect in ERN1-deficient cells. Glucose deprivation condition leads to a decrease of expression levels of retinoblastoma, RBL1, E2F3, RBAP46, and RBAP48 in both used cell types and of EID1 and E2F1 only in glioma cells with suppressed function of signaling enzyme ERN1. Thus, expression levels of retinoblastoma and most retinoblastoma-related genes are increased under a blockade of ERN1 enzyme function and significantly changed in hypoxia, glucose or glutamine deprivation conditions both in control u87 cells and ERN1-deficient cells, but inhibition of the unfolded protein response sensor ERN1 predominantly enhances these effects. Mor

关键词： mRNA Expression Retinoblastoma RBL1 RBAP48 RBAP46 CTIP KDM5A JARID1B E2F1 E2F3 Glioma Cells ERN1 Hypoxia Glucose Deprivation Glutamine Deprivation

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Human IgG1 antibodies suppress angiogenesis in a target-independent manner

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Signal Transduction and Targeted Therapy 2016年第1期1卷 158-171页

作者： Sasha Bogdanovich Younghee Kim Takeshi Mizutani Reo Yasuma Laura Tudisco Valeria Cicatiello Ana Bastos-Carvalho Nagaraj Kerur Yoshio Hirano Judit Z Baffi Valeria Tarallo Shengjian Li Tetsuhiro Yasuma Parthasarathy Arpitha Benjamin J Fowler Charles B Wright Ivana Apicella Adelaide Greco Arturo Brunetti Menotti Ruvo Annamaria Sandomenico Miho Nozaki Ryo Ijima Hiroki Kaneko Yuichiro Ogura Hiroko Terasaki Balamurali K Ambati Jeanette HW Leusen Wallace Y Langdon Michael R Clark Kathryn L Armour Pierre Bruhns J Sjef Verbeek Bradley D Gelfand Sandro De Falco Jayakrishna Ambati Department of Ophthalmology and Visual Sciences University of KentuckyLexingtonKYUSA Department of Ophthalmology and Visual Science Nagoya City University Graduate School of Medical SciencesNagoyaJapan Department of Ophthalmology Nagoya University Graduate School of MedicineNagoyaJapan angiogenesis Lab Institute of Genetics and Biophysics—CNRNaplesItaly Bio-Ker MultiMedica GroupNaplesItaly Department of Advanced Biomedical Sciences University of Naples‘Federico II’NaplesItaly CEINGE—Biotecnologie Avanzate s.c.a.r.l.NaplesItaly Istituto di Biostrutture e Bioimmagini CNRNaplesItaly Department of Ophthalmology and Visual Sciences Moran Eye CenterUniversity of Utah School of MedicineSalt Lake CityUTUSA Department of Ophthalmology Veterans Affairs Salt Lake City Healthcare SystemSalt Lake CityUTUSA Immunotherapy laboratory Laboratory for Translational ImmunologyUniversity Medical Center UtrechtUtrechtThe Netherlands School of Pathology and laboratory Medicine University of Western AustraliaCrawleyWAAustralia Division of Immunology Department of PathologyUniversity of CambridgeCambridgeUK Department of Immunology Unit of Antibodies in Therapy and PathologyInstitut PasteurParisFrance Institut National de la Santéet de la Recherche Médicale(inserm)u1222 ParisFrance Department of Human Genetics Leiden University Medical CenterLeidenThe Netherlands Department of Biomedical Engineering University of KentuckyLexingtonKYUSA Department of Microbiology Immunologyand Molecular GeneticsUniversity of KentuckyLexingtonKYUSA IRCCS MultiMedica MilanoItaly Department of Physiology University of KentuckyLexingtonKYUSA.

Aberrant angiogenesis is implicated in diseases affecting nearly 10%of the world’s *** most widely used antiangiogenic drug is bevacizumab,a humanized IgG1 monoclonal antibody that targets human *** bevacizumab does not recognize mouse Vegfa,it inhibits angiogenesis in *** we show bevacizumab suppressed angiogenesis in three mouse models not via Vegfa blockade but rather Fc-mediated signaling through FcγRI(CD64)and c-Cbl,impairing macrophage *** approved humanized or human IgG1 antibodies without mouse targets(adalimumab,alemtuzumab,ofatumumab,omalizumab,palivizumab and tocilizumab),mouse IgG2a,and overexpression of human IgG1-Fc or mouse IgG2a-Fc,also inhibited angiogenesis in wild-type and FcγR humanized *** anti-angiogenic effect was abolished by Fcgr1 ablation or knockdown,Fc cleavage,IgG-Fc inhibition,disruption of Fc-FcγR interaction,or elimination of FcRγ-initated ***,bevacizumab’s Fc region potentiated its anti-angiogenic activity in humanized VEGFA ***,mice deficient in FcγRI exhibited increased developmental and pathological *** findings reveal an unexpected anti-angiogenic function for FcγRI and a potentially concerning off-target effect of hIgG1 therapies.

关键词： CD64 angiogenesis antibodies

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