Cancer Chemotherapy and Pharmacology

, Volume 68, Issue 3, pp 619–629

Cytochrome P450 ω-hydroxylase promotes angiogenesis and metastasis by upregulation of VEGF and MMP-9 in non-small cell lung cancer

  • Wei Yu
  • Li Chen
  • Yu-Qing Yang
  • John R. Falck
  • Austin M. Guo
  • Ying Li
  • Jing Yang
Original Article

DOI: 10.1007/s00280-010-1521-8

Cite this article as:
Yu, W., Chen, L., Yang, YQ. et al. Cancer Chemother Pharmacol (2011) 68: 619. doi:10.1007/s00280-010-1521-8

Abstract

Purpose

Cytochrome P450 (CYP) ω-hydroxylase, mainly consisting of CYP4A and CYP4F, converts arachidonic acid to 20-hydroxyeicosatetraenoic acid (20-HETE) that induces angiogenic responses in vivo and in vitro. The present study examined the role of CYP ω-hydroxylase in angiogenesis and metastasis of human non-small cell lung cancer (NSCLC).

Methods

The effect of WIT003, a stable 20-HETE analog, on invasion was evaluated using a modified Boyden chamber in three NSCLC cell lines. A549 cells were transfected with CYP4A11 expression vector or exposed to CYP ω-hydroxylase inhibitor (HET0016) or 20-HETE antagonist (WIT002), and then ω-hydroxylation activity toward arachidonic acid and the levels of matrix metalloproteinases (MMPs) and VEGF were detected. The in vivo effects of CYP ω-hydroxylase were tested in established tumor xenografts and an experimental metastasis model in athymic mice.

Results

Addition of WIT003 or overexpression of CYP4A11 with an associated increase in 20-HETE production significantly induced invasion and expression of VEGF and MMP-9. Treatment of A549 cells with HET0016 or WIT002 inhibited invasion with reduction in VEGF and MMP-9. The PI3 K or ERK inhibitors also attenuated expression of VEGF and MMP-9. Compared with control, CYP4A11 transfection significantly increased tumor weight, microvessel density (MVD), and lung metastasis by 2.5-fold, 2-fold, and 3-fold, respectively. In contrast, WIT002 or HET0016 decreased tumor volume, MVD, and spontaneous pulmonary metastasis occurrences.

Conclusion

CYP ω-hydroxylase promotes tumor angiogenesis and metastasis by upregulation of VEGF and MMP-9 via PI3 K and ERK1/2 signaling in human NSCLC cells.

Keywords

Cytochrome P450 20-HETE Metastasis Angiogenesis NSCLC 

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Wei Yu
    • 1
  • Li Chen
    • 1
  • Yu-Qing Yang
    • 2
  • John R. Falck
    • 3
  • Austin M. Guo
    • 4
  • Ying Li
    • 1
  • Jing Yang
    • 1
  1. 1.Department of Pharmacology, School of MedicineWuhan UniversityWuhanChina
  2. 2.School of PharmacyChina Pharmaceutical UniversityNanjingChina
  3. 3.University of Texas Southwestern Medical CenterDallasUSA
  4. 4.Department of Women’s Health Services, Gynecologic OncologyHenry Ford Health SystemDetroitUSA

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