Embelin inhibits endothelial mitochondrial respiration and impairs neoangiogenesis during tumor growth and wound healing

EMBO Molecular Medicine

Volumn 6, Issue 5, 2014, Pages 624-639

  Coutelle, Oliver ^a   Hornig Do, Hue Tran ^a   Witt, Axel ^a   Andree, Maria ^a   Schiffmann, Lars M ^a   Piekarek, Michael ^a   Brinkmann, Kerstin ^a   Seeger, Jens M ^a   Liwschitz, Maxim ^a   Miwa, Satomi ^b   Hallek, Michael ^a   Krönke, Martin ^a,c   Trifunovic, Aleksandra ^c   Eming, Sabine A ^a,c   Wiesner, Rudolf J ^a,c   Hacker, Ulrich T ^a   Kashkar, Hamid ^a,c  

^a UNIVERSITY OF COLOGNE   (Germany)

^b NEWCASTLE UNIVERSITY   (United Kingdom)

^c UNIVERSITY OF COLOGNE   (Germany)

Author keywords

Angiogenesis; Embelin; Mitochondria; Tumor; Uncoupler; Wound healing; Xenograft

Indexed keywords

ADENOSINE TRIPHOSPHATE; ALPHA SMOOTH MUSCLE ACTIN; BUTYLCRESOL; CYTOCHROME C; EMBELIN; ENDOGLIN; FIBROBLAST GROWTH FACTOR; KI 67 ANTIGEN; MITOCHONDRIAL DNA; OXAMIC ACID; PIMONIDAZOLE; PROTON; VASCULAR ENDOTHELIAL CADHERIN; VASCULOTROPIN; ANTINEOPLASTIC AGENT; BENZOQUINONE DERIVATIVE; UNCOUPLING PROTEIN;

ANGIOGENESIS; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTIANGIOGENIC ACTIVITY; ANTINEOPLASTIC ACTIVITY; ARTICLE; BASEMENT MEMBRANE; CAPILLARY DENSITY; CELL DEATH; CELL PROLIFERATION; CELL VIABILITY; CLONOGENESIS; CONTROLLED STUDY; CYTOTOXICITY; DOWN REGULATION; ENDOTHELIUM CELL; EPITHELIZATION; GLYCOLYSIS; GRANULATION TISSUE; HUMAN; HUMAN CELL; HYPOXIA; IMMUNOHISTOCHEMISTRY; MACROPHAGE; MICROVASCULAR ENDOTHELIAL CELL; MITOCHONDRIAL MEMBRANE POTENTIAL; MITOCHONDRIAL RESPIRATION; MOUSE; MYOFIBROBLAST; NEOANGIOGENESIS; NEUTROPHIL; NONHUMAN; OXIDATIVE PHOSPHORYLATION; OXIDATIVE PHOSPHORYLATION UNCOUPLING; OXYGEN CONSUMPTION; PERICYTE; PRIORITY JOURNAL; PROTEIN EXPRESSION; RESPIRATORY CHAIN; SKIN INJURY; TUMOR GROWTH; TUMOR VASCULARIZATION; UMBILICAL VEIN ENDOTHELIAL CELL; UPREGULATION; WOUND CLOSURE; WOUND HEALING; ANIMAL; CELL RESPIRATION; DISEASE MODEL; DRUG EFFECTS; METABOLISM; MITOCHONDRION; NEOPLASMS; NEOVASCULARIZATION (PATHOLOGY);

ANIMALS; ANTINEOPLASTIC AGENTS; BENZOQUINONES; CELL RESPIRATION; DISEASE MODELS, ANIMAL; ENDOTHELIAL CELLS; MICE; MITOCHONDRIA; NEOPLASMS; NEOVASCULARIZATION, PATHOLOGIC; NEOVASCULARIZATION, PHYSIOLOGIC; UNCOUPLING AGENTS; WOUND HEALING;

EID: 84899973055     PISSN: 17574676     EISSN: 17574684     Source Type: Journal    
DOI: 10.1002/emmm.201303016     Document Type: Article

References (51)

1. Adams RL, Adams IP, Lindow SW, Zhong W, Atkin SL (2005) Somatostatin receptors 2 and 5 are preferentially expressed in proliferating endothelium. Br J Cancer 92: 1493-1498
2. Ahn KS, Sethi G, Aggarwal BB (2007) Embelin, an inhibitor of X chromosome-linked inhibitor-of-apoptosis protein, blocks nuclear factor-kappaB (NF-kappaB) signaling pathway leading to suppression of NF-kappaB-regulated antiapoptotic and metastatic gene products. Mol Pharmacol 71: 209-219
3. Allensworth JL, Aird KM, Aldrich AJ, Batinic-Haberle I, Devi GR (2012) XIAP inhibition and generation of reactive oxygen species enhances TRAIL sensitivity in inflammatory breast cancer cells. Mol Cancer Ther 11: 1518-1527
4. Anderson S, Bankier AT, Barrell BG, de Bruijn MH, Coulson AR, Drouin J, Eperon IC, Nierlich DP, Roe BA, Sanger F et al (1981) Sequence and organization of the human mitochondrial genome. Nature 290: 457-465
5. Birket MJ, Orr AL, Gerencser AA, Madden DT, Vitelli C, Swistowski A, Brand MD, Zeng X (2011) A reduction in ATP demand and mitochondrial activity with neural differentiation of human embryonic stem cells. J Cell Sci 124: 348-358
6. Brand MD (2005) The efficiency and plasticity of mitochondrial energy transduction. Biochem Soc Trans 33: 897-904
7. Brand MD, Nicholls DG (2011) Assessing mitochondrial dysfunction in cells. Biochem J 435: 297-312
8. Chance B, Williams GR (1956) The respiratory chain and oxidative phosphorylation. Adv Enzymol Relat Subj Biochem 17: 65-134
9. Chitra M, Sukumar E, Suja V, Devi CS (1994) Antitumor, anti-inflammatory and analgesic property of embelin, a plant product. Chemotherapy 40: 109-113
10. Dagher Z, Ruderman N, Tornheim K, Ido Y (2001) Acute regulation of fatty acid oxidation and AMP-activated protein kinase in human umbilical vein endothelial cells. Circ Res 88: 1276-1282
11. Dai Y, Qiao L, Chan KW, Yang M, Ye J, Ma J, Zou B, Gu Q, Wang J, Pang R et al (2009) Peroxisome proliferator-activated receptor-gamma contributes to the inhibitory effects of Embelin on colon carcinogenesis. Cancer Res 69: 4776-4783
12. De Bock K, Georgiadou M, Carmeliet P (2013a) Role of endothelial cell metabolism in vessel sprouting. Cell Metab 18: 634-647
13. De Bock K, Georgiadou M, Schoors S, Kuchnio A, Wong BW, Cantelmo AR, Quaegebeur A, Ghesquiere B, Cauwenberghs S, Eelen G et al (2013b) Role of PFKFB3-driven glycolysis in vessel sprouting. Cell 154: 651-663
14. De Smet F, Segura I, De Bock K, Hohensinner PJ, Carmeliet P (2009) Mechanisms of vessel branching: filopodia on endothelial tip cells lead the way. Arterioscler Thromb Vasc Biol 29: 639-649
15. Denekamp J, Hobson B (1982) Endothelial-cell proliferation in experimental tumours. Br J Cancer 46: 711-720
16. Dobrina A, Rossi F (1983) Metabolic properties of freshly isolated bovine endothelial cells. Biochim Biophys Acta 762: 295-301
17. Edgar D, Shabalina I, Camara Y, Wredenberg A, Calvaruso MA, Nijtmans L, Nedergaard J, Cannon B, Larsson NG, Trifunovic A (2009) Random point mutations with major effects on protein-coding genes are the driving force behind premature aging in mtDNA mutator mice. Cell Metab 10: 131-138
18. Elmasri H, Karaaslan C, Teper Y, Ghelfi E, Weng M, Ince TA, Kozakewich H, Bischoff J, Cataltepe S (2009) Fatty acid binding protein 4 is a target of VEGF and a regulator of cell proliferation in endothelial cells. FASEB J 23: 3865-3873
19. Fonsatti E, Altomonte M, Nicotra MR, Natali PG, Maio M (2003) Endoglin (CD105): a powerful therapeutic target on tumor-associated angiogenetic blood vessels. Oncogene 22: 6557-6563
20. Gupta OP, Ali MM, Ray Ghatak BJ, Atal CK (1977) Some pharmacological investigations of embelin and its semisynthetic derivatives. Indian J Physiol Pharmacol 21: 31-39
21. Hanahan D, Folkman J (1996) Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86: 353-364
22. Harjes U, Bensaad K, Harris AL (2012) Endothelial cell metabolism and implications for cancer therapy. Br J Cancer 107: 1207-1212
23. Harper JA, Dickinson K, Brand MD (2001) Mitochondrial uncoupling as a target for drug development for the treatment of obesity. Obes Rev 2: 255-265
24. Hirayama A, Kami K, Sugimoto M, Sugawara M, Toki N, Onozuka H, Kinoshita T, Saito N, Ochiai A, Tomita M et al (2009) Quantitative metabolome profiling of colon and stomach cancer microenvironment by capillary electrophoresis time-of-flight mass spectrometry. Cancer Res 69: 4918-4925
25. Joy B, Sivadasan R, Abraham ET, Mohan J, Sobhan PK, Seervi M, Santoshkumar TR (2010) Lysosomal destabilization and cathepsin B contributes for cytochrome c release and caspase activation in embelin-induced apoptosis. Mol Carcinog 49: 324-336
26. Krützfeldt A, Spahr R, Mertens S, Siegmund B, Piper HM (1990) Metabolism of exogenous substrates by coronary endothelial cells in culture. J Mol Cell Cardiol 22: 1393-1404
27. Kurz DJ, Hong Y, Trivier E, Huang HL, Decary S, Zang GH, Luscher TF, Erusalimsky JD (2003) Fibroblast growth factor-2, but not vascular endothelial growth factor, upregulates telomerase activity in human endothelial cells. Arterioscler Thromb Vasc Biol 23: 748-754
28. Lebrin F, Goumans MJ, Jonker L, Carvalho RL, Valdimarsdottir G, Thorikay M, Mummery C, Arthur HM, ten Dijke P (2004) Endoglin promotes endothelial cell proliferation and TGF-beta/ALK1 signal transduction. EMBO J 23: 4018-4028
29. Leighton B, Curi R, Hussein A, Newsholme EA (1987) Maximum activities of some key enzymes of glycolysis, glutaminolysis, Krebs cycle and fatty acid utilization in bovine pulmonary endothelial cells. FEBS Lett 225: 93-96
30. Lou PH, Hansen BS, Olsen PH, Tullin S, Murphy MP, Brand MD (2007) Mitochondrial uncouplers with an extraordinary dynamic range. Biochem J 407: 129-140
31. Lucas T, Waisman A, Ranjan R, Roes J, Krieg T, Muller W, Roers A, Eming SA (2010) Differential roles of macrophages in diverse phases of skin repair. J Immunol 184: 3964-3977
32. Mahboubi K, Li F, Plescia J, Kirkiles-Smith NC, Mesri M, Du Y, Carroll JM, Elias JA, Altieri DC, Pober JS (2001) Interleukin-11 up-regulates survivin expression in endothelial cells through a signal transducer and activator of transcription-3 pathway. Lab Invest 81: 327-334
33. Makawiti DW, Konji VN, Olowookere JO (1990) Interaction of benzoquinones with mitochondria interferes with oxidative phosphorylation characteristics. FEBS Lett 266: 26-28
34. Mariotti M, Castiglioni S, Bernardini D, Maier JA (2006) Interleukin 1 alpha is a marker of endothelial cellular senescent. Immun Ageing 3: 4
35. Mertens S, Noll T, Spahr R, Krutzfeldt A, Piper HM (1990) Energetic response of coronary endothelial cells to hypoxia. Am J Physiol 258: H689-H694
36. Nikolovska-Coleska Z, Xu L, Hu Z, Tomita Y, Li P, Roller PP, Wang R, Fang X, Guo R, Zhang M et al (2004) Discovery of embelin as a cell-permeable, small-molecular weight inhibitor of XIAP through structure-based computational screening of a traditional herbal medicine three-dimensional structure database. J Med Chem 47: 2430-2440
37. Niu X, Trifunovic A, Larsson NG, Canlon B (2007) Somatic mtDNA mutations cause progressive hearing loss in the mouse. Exp Cell Res 313: 3924-3934
38. Norddahl GL, Pronk CJ, Wahlestedt M, Sten G, Nygren JM, Ugale A, Sigvardsson M, Bryder D (2011) Accumulating mitochondrial DNA mutations drive premature hematopoietic aging phenotypes distinct from physiological stem cell aging. Cell Stem Cell 8: 499-510
39. Papaconstantinou J, Colowick SP (1961) The role of glycolysis in the growth of tumor cells. I. Effects of oxamic acid on the metabolism of Ehrlich ascites tumor cells in vitro. J Biol Chem 236: 278-284
40. Parra-Bonilla G, Alvarez DF, Al-Mehdi A-B, Alexeyev M, Stevens T (2010) Critical role for lactate dehydrogenase A in aerobic glycolysis that sustains pulmonary microvascular endothelial cell proliferation. Am J Physiol Lung Cell Mol Physiol 299: L513-L522
41. Potente M, Ghaeni L, Baldessari D, Mostoslavsky R, Rossig L, Dequiedt F, Haendeler J, Mione M, Dejana E, Alt FW et al (2007) SIRT1 controls endothelial angiogenic functions during vascular growth. Genes Dev 21: 2644-2658
42. Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM, Puigserver P (2005) Nutrient control of glucose homeostasis through a complex of PGC-1[alpha] and SIRT1. Nature 434: 113-118
43. Rustin P, Chretien D, Bourgeron T, Gerard B, Rotig A, Saudubray JM, Munnich A (1994) Biochemical and molecular investigations in respiratory chain deficiencies. Clin Chim Acta 228: 35-51
44. Shweiki D, Itin A, Soffer D, Keshet E (1992) Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 359: 843-845
45. Spolarics Z, Lang CH, Bagby GJ, Spitzer JJ (1991) Glutamine and fatty acid oxidation are the main sources of energy for Kupffer and endothelial cells. Am J Physiol 261: G185-G190
46. Tannock IF, Hayashi S (1972) The proliferation of capillary endothelial cells. Cancer Res 32: 77-82
47. Trifunovic A, Hansson A, Wredenberg A, Rovio AT, Dufour E, Khvorostov I, Spelbrink JN, Wibom R, Jacobs HT, Larsson NG (2005) Somatic mtDNA mutations cause aging phenotypes without affecting reactive oxygen species production. Proc Natl Acad Sci USA 102: 17993-17998
48. Trifunovic A, Wredenberg A, Falkenberg M, Spelbrink JN, Rovio AT, Bruder CE, Bohlooly YM, Gidlof S, Oldfors A, Wibom R et al (2004) Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 429: 417-423
49. Tsai AG, Friesenecker B, Mazzoni MC, Kerger H, Buerk DG, Johnson PC, Intaglietta M (1998) Microvascular and tissue oxygen gradients in the rat mesentery. Proc Natl Acad Sci USA 95: 6590-6595
50. Vag T, Schramm T, Kaiser WA, Hilger I (2009) Proliferating and quiescent human umbilical vein endothelial cells (HUVECs): a potential in vitro model to evaluate contrast agents for molecular imaging of angiogenesis. Contrast Media Mol Imaging 4: 192-198
51. Yuan F, Chen Y, Dellian M, Safabakhsh N, Ferrara N, Jain RK (1996) Time-dependent vascular regression and permeability changes in established human tumor xenografts induced by an anti-vascular endothelial growth factor/vascular permeability factor antibody. Proc Natl Acad Sci USA 93: 14765-14770