Autocrine Vascular Endothelial Growth Factor/Vascular Endothelial Growth Factor Receptor-2 Growth Pathway Represents a Cyclooxygenase-2-Independent Target for the Cyclooxygenase-2 Inhibitor NS-398 in Colon Cancer Cells

Vol. 68, No. 2-3, 2005

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Laboratory Investigation

Autocrine Vascular Endothelial Growth Factor/Vascular Endothelial Growth Factor Receptor-2 Growth Pathway Represents a Cyclooxygenase-2-Independent Target for the Cyclooxygenase-2 Inhibitor NS-398 in Colon Cancer Cells
Seok Jin Kim^a, Jae Hong Seo^a, Yoo Jung Lee^b, Ji Hye Yoon^b, Chul Won Choi^a, Byung Soo Kim^a, Sang Won Shin^a, Yeul Hong Kim^a, Jun Suk Kim^a

^aDivision of Oncology and Hematology, Department of Internal Medicine, College of Medicine, and
^bGraduate School of Medicine, Korea University, Seoul, Korea

Address of Corresponding Author

Oncology 2005;68:204-211 (DOI: 10.1159/000086775)

Key Words

Cyclooxygenase-2 inhibitor
VEGF/VEGFR-2 growth pathway, autocrine
Cyclooxygenase-2-independent target
Colon cancer cell

Abstract

Objectives: Coexpression of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor-2 (VEGFR-2) has been reported in tumor cells, suggesting the presence of an autocrine VEGF/VEGFR-2 growth pathway in solid tumors. Thus, we hypothesize that the presence of this autocrine pathway in colon cancer cells may be a COX-2-independent target of COX-2 inhibitors and a mechanism behind the antitumor effects of these agents. Methods: COX-2-positive (Caco2, HT-29) and COX-2-negative colon cancer cells (DLD-1, Hct-15) were used. Expression of VEGFR-2 was evaluated by Western blot and reverse transcriptase-polymerase chain reaction and VEGF production was measured from culture supernatant by enzyme-linked immunosorbent assay. Growth inhibition and the expression of VEGF and VEGFR-2 were compared after treatment with the COX-2 inhibitor, NS-398 at doses ranging from 5 to 100 µM. Results: VEGF and VEGFR-2 were expressed in all four colon cancer cells and a blockade of VEGFR-2 with anti-VEGFR-2 antibody treatment induced growth inhibition of colon cancer cells, supporting the presence of autocrine VEGF/VEGFR-2 growth pathway. NS-398 suppressed the growth of colon cancer cells, independent of COX-2 expression. VEGFR-2 expression of tumor cells was reduced after NS-398 treatment at 100 µM, the concentration at which maximal growth inhibition was induced. The amount of VEGF in culture supernatant was increased by NS-398 at 100 µM, suggesting increased secretion of VEGF in compensation for reduced VEGFR-2 expression. Conclusion: The autocrine VEGF/VEGFR-2 growth pathway could be a COX-2-independent target of the COX-2 inhibitor, NS-398, in colon cancer cells.

Author Contacts

Jae Hong Seo, MD, PhD
Division of Oncology and Hematology, Department of Internal Medicine
Ansan Hospital, Korea University Medical Center, 516, Kozan-1 Dong
Ansan City, Kyoung-ki, 425-707 (Korea)
Tel. +82 31 412 5886, Fax +82 31 412 5806, E-Mail cancer@korea.ac.kr

Article Information

Received: March 27, 2004
Accepted after revision: July 5, 2004
Published online: July 7, 2005
Number of Print Pages : 8
Number of Figures : 8, Number of Tables : 0, Number of References : 23

Medline Abstract (ID 16015035)

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