Skip to main content
SpringerLink
Log in

P-450-dependent epoxygenase pathway of arachidonic acid is involved in myeloma-induced angiogenesis of endothelial cells

  • Published:
Journal of Huazhong University of Science and Technology [Medical Sciences] Aims and scope Submit manuscript

Summary

P-450-dependent epoxygenase pathway of arachidonic acid and the products of epoxyeicosatrienoic acids (EETs) have been demonstrated to be involved in angiogenesis and tumor progression. This study examined the expression of EETs and the role of the pathway in the angiogenesis of multiple myeloma (MM). MM cell lines of U266 and RPMI8226 were cultured, and the EETs levels (11, 12-EET and 14, 15-EET) in the supernatant were determined by ELISA. Human umbilical vein endothelial cells (HUVECs) were cultured and used for analysis of the angiogenesis activity of the two MM cell lines, which was examined both in vitro and in vivo by employing MTT, chemotaxis, tube formation and matrigel plug assays. 11, 12-EET and 14, 15-EET were found in the supernatant of the cultured MM cells. The levels of the two EETs in the supernatant of U266 cells were significantly higher than those in the RPMI8226 cell supernatant (P<0.05), and the levels paralleled the respective angiogenesis activity of the two different MM cell lines. 17-octadecynoic acid (17-ODYA), as a specific inhibitor of P450 enzyme, suppressed HUVECs proliferation and tube formation induced by MM cells. Furthermore, 17-ODYA decreased the EET levels in the supernatant of MM cells. These results suggest that EETs may play an important role in the angiogenesis of MM, and the inhibitor 17-ODYA suppresses this effect.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Vacca A, Ribatti D, Roncali L, et al. Bone marrow angiogenesis and progression in multiple myeloma. Br J Haematol, 1994,87(3):503–508

    Article  PubMed  CAS  Google Scholar 

  2. Rajkumar SV, Leong T, Roche PC, et al. Prognostic value of bone marrow angiogenesis in multiple myeloma. Clin Cancer Res, 2000,6(8):3111–3116

    PubMed  CAS  Google Scholar 

  3. Pruneri G, Ponzoni M, Ferreri AJ, et al. Microvessel density, a surrogate marker of angiogenesis, is signific antly related to survival in multiple myeloma patients. Br J Haematol, 2002,118(3):817–820

    Article  PubMed  Google Scholar 

  4. Gupta D, Treon SP, Shima Y, et al. Adherence of multiple myeloma cells to bone marrow stromal cells upregulates vascular endothelial growth facter secretion: therapeutic applications. Leukemia, 2001,15(12):1950–1961

    Article  PubMed  CAS  Google Scholar 

  5. Dankbar B, Padró T, Leo R, et al. Vascular endothelial growth factor and interleukin-6 in paracrine tumor-stromal cell interactions in multiple myeloma. Blood, 2000,95(8): 2630–2636

    PubMed  CAS  Google Scholar 

  6. Podar K, Anderson KC. The pathophysiologic role of VEGF in hematologic malignancies: therapeutic implications. Blood, 2005,105(4):1383–1395

    Article  PubMed  CAS  Google Scholar 

  7. Xu JL, Lai R, Kinoshita T, et al. Proliferation, apoptosis, and intratumoral vascularity in multiple myeloma: correlation with the clinical stage and cytological grade. J Clin Pathol, 2002,55(7):530–534

    Article  PubMed  CAS  Google Scholar 

  8. Rajkumar SV, Mesa RA, Fonseca R, et al. Bone marrow angiogenesis in 400 patients with monoclonal gammop athy of undetermined significance, multiple myeloma, and primary amyloidosis. Clin Cancer Res, 2002,8(7):2210–2216

    PubMed  Google Scholar 

  9. Michaelis UR, Fisslthaler B, Barbosa-Sicard E, et al. Cytochrome P450 epoxygenases 2C8 and 2C9 are implicated in hypoxia-induced endothelial cell migration and angiogenesis. J Cell Sci, 2005,118(Pt23):5489–5498

    Article  PubMed  CAS  Google Scholar 

  10. Michealis UR, Fleming I. From endothelium-derived hyperpolarizing factor (EDHF) to angiogenesis: epoxyeicosatrienoic acids (EETs) and cell signaling. Pharmacol Ther, 2006,111(3):584–595

    Article  Google Scholar 

  11. Potente M, Fisslthaler B, Busse R, et al. 11,12-epoxyeicosatrienoic acid-induced inhibition of FOXO factors promotes endothelial proliferation by downregulating p27Kip1. J Biol Chem, 2003,278(32):29619–29625

    Article  PubMed  CAS  Google Scholar 

  12. Yan G, Chen S, You B, et al. Activation of sphingosine kinase-1 mediates induction of endothelial cell proliferation and angiogenesis by epoxyeicosatrienoic acids. Cardiovasc Res, 2008,78(2):308–314

    Article  PubMed  CAS  Google Scholar 

  13. Michaelis UR, Falck JR, Schmidt R, et al. Cytochrome P4502C9-derived epoxyeicosatrienoic acids induce the expression of cyclooxygenase-2 in endothelial cells. Arterioscler Thromb Vasc Biol, 2005,25(2):321–326

    Article  PubMed  CAS  Google Scholar 

  14. Chen JK, Capdevila J, Harris RC. Heparin-binding EGF-like growth factor mediates the biological effects of P450 arachidonate epoxygenase metabolites in epithelial cells. Proc Natl Acad Sci USA, 2002,99(9):6029–6034

    Article  PubMed  CAS  Google Scholar 

  15. Michaelis UR, Fisslthaler B, Medhora M, et al. Cytochrome P450 2C9-derived epoxyeicosatrienoic acids induce angiogenesis via cross-talk with the epidermal growth factor receptor (EGFR). FASEB J, 2003,17(6): 770–772

    PubMed  CAS  Google Scholar 

  16. Jiang JG, Ning YG, Chen C, et al. Cytochrome p450 epoxygenase promotes human cancer metastasis. Cancer Res, 2007,67(14):6665–6674

    Article  PubMed  CAS  Google Scholar 

  17. Zagorac D, Jakovcevic D, Gebremedhin D, et al. Antiangiogenic effect of inhibitors of cytochrome P450 on rats with glioblastoma multiforme. J Cereb Blood Flow Metab, 2008,28(8):1431–1439

    Article  PubMed  CAS  Google Scholar 

  18. Kim YM, Kim YM, Lee YM, et al. TNF-related activation-induced cytokine (TRANCE) induces angiogenesis through the activation of Src and phospholipase C (PLC) in human endothelial cells. J Biol Chem, 2002,277(9):6799–6805

    Article  PubMed  CAS  Google Scholar 

  19. Yahata Y, Shirakata Y, Tokumaru S, et al. Nuclear translocation of phosphorylates STAT3 is essential for vascular endothelial growth factor-induced human dermal microvascular endothelial cell migration and tube formation. J Biol Chem, 2003,278(41):40026–40031

    Article  PubMed  CAS  Google Scholar 

  20. Zhang C, Harder DR. Cerebral capillary endothelial cell mitogenesis and morphogenesis induced by astrocytic epoxyeicosatrienoic acid. Stroke, 2002,33(12):2957–2964

    Article  PubMed  CAS  Google Scholar 

  21. Wang Y, Wei X, Xiao X, et al. Arachidonic acid epoxygenase metabolites stimulate endothelial cell growth and angiogenesis via mitogen-activated protein kinase and phosohatidylinositol 3-kinase/Akt signaling pathways. J Pharmacol Exp Ther, 2005,314(2):522–532

    Article  PubMed  CAS  Google Scholar 

  22. Capdevila JH, Falck JR, Harris RC. Cytochrome P450 and arachidonic acid bioactivation. Molecular and functional properties of the arachidonate monooxygenase. J Lipid Res, 2000,41(2):163–181

    PubMed  CAS  Google Scholar 

  23. Karara A, Dishman E, Jacobson H, et al. Arachidonic acid epoxygenase. Steraochemical analysis of the endogenous epoxyeicosatrienoic acids of human kidney cortex. FEBS Lett, 1990,268(1):227–230

    Article  PubMed  CAS  Google Scholar 

  24. Karara A, Dishman E, Falck JR, et al. Endogenous epoxyeicossatrienoyl-phospholipids. A novel class of cellular glycerolipids containing epoxidized arachidonate moieties. J Biol Chem, 1991, 266(12):7561–7569

    PubMed  CAS  Google Scholar 

  25. Spector AA, Norris AW. Action of epoxyeicosatrienoic acids on cellular function. Am J Physiol Cell Physiol, 2007,292(3):C996–C1012

    Article  PubMed  CAS  Google Scholar 

  26. Spector AA, Fang X, Snyder GD, et al. Epoxyeicosatrienoic acids (EETs): metabolism and biochemical function. Prog Lipid Res, 2004,43(1):55–90

    Article  PubMed  CAS  Google Scholar 

  27. Fleming I, Busse R. Endothelium-derived epoxyeicosatrienoic acids and vascular function. Hypertension, 2006,47(4):629–633

    Article  PubMed  CAS  Google Scholar 

  28. Wong PY, Lai PS, Falck JR. Mechanism and signal transduction of 14(R), 15(S)-epoxyeicosatrienoic acid (14, 15-EET) binding in guinea pig monocytes. Prostaglandins Other Lipid Mediat, 2000,62(4):321–333

    Article  PubMed  CAS  Google Scholar 

  29. Wong PY, Lai PS, Shen SY, et al. Post-receptor signal transduction and regulation of 14(R), 15(S)-epoxyeicos atrienoic acid (14, 15-EET) binding in U-937 cells. J Lipid Mediat Cell Signal, 1997,16(3):155–169

    Article  PubMed  CAS  Google Scholar 

  30. Wong PY, Lin KT, Yan YT, et al. 14(R), 15(S)-epoxyeicosatrienoic acid (14(R), 15(S)-EET) receptor in guinea pig mononuclear cell membranes. J Lipid Mediat, 1993,6(1–3): 199–208

    PubMed  CAS  Google Scholar 

  31. Cheranov SY, Karpurapu M, Wang D, et al. An essential role for SRC-activated STAT-3 in 14, 15-EET-induced VEGF expression and angiogenesis. Blood, 2008,111(12): 5581–5591

    Article  PubMed  CAS  Google Scholar 

  32. Webler AC, Michaelis UR, Popp R, et al. Epoxyeicosatrienoic acids are part of the VEGF-activated signaling cascade leading to angiogenesis. Am J Physiol Cell Physiol, 2008,295(5):C1292–C1301

    Article  PubMed  CAS  Google Scholar 

  33. Zheng M, Sun H, Zhou J, et al. Proliferation and apoptosis of bone marrow CD4(+) T cells in patients with aplastic anemia and impacts of the secreted cytokines on hematopoietic stem cells from umbilical cord blood. J Huazhong Univ Sci Technolog [Med Sci], 2010,30(1): 37–41

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    Jing Shao  (邵 菁), Qiubai Li  (李秋柏), Fang Liu  (刘 芳), Xiaojian Zhu  (朱晓健), Zhichao Chen  (陈智超) & Ping Zou  (邹 萍)

  2. Department of Hematology, Wuhan Central Hospital, Wuhan, 430014, China

    Hongxiang Wang  (王红祥)

  3. Department of Internal Medicine and Gene Therapy Center, Tongji Hospital, Tongji Medical College, Huazhong University of Scienceand Technology, Wuhan, 430030, China

    Jiangang Jiang  (蒋建刚)

Authors
  1. Jing Shao  (邵 菁)
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Qiubai Li  (李秋柏)
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hongxiang Wang  (王红祥)
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Fang Liu  (刘 芳)
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jiangang Jiang  (蒋建刚)
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xiaojian Zhu  (朱晓健)
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Zhichao Chen  (陈智超)
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ping Zou  (邹 萍)
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Zhichao Chen  (陈智超) or Ping Zou  (邹 萍).

Additional information

This project was supported by grants from the National Natural Science Foundation of China (No. 81071943) and the Foundation of Natural Sciences of Hubei Province of China (No. 2007ABA072).

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shao, J., Li, Q., Wang, H. et al. P-450-dependent epoxygenase pathway of arachidonic acid is involved in myeloma-induced angiogenesis of endothelial cells. J. Huazhong Univ. Sci. Technol. [Med. Sci.] 31, 596–601 (2011). https://doi.org/10.1007/s11596-011-0567-0

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11596-011-0567-0

Key words

Search

Navigation