Vascular endothelial growth factor-C modulates proliferation and chemoresistance in acute myeloid leukemic cells through an endothelin-1-dependent induction of cyclooxygenase-2

Kuo-Tai Hua; Wei-Jiunn Lee; Shun-Fa Yang; Chi-Kuan Chen; Michael Hsiao; Chia-Chi Ku; Lin-Hung Wei; Min-Liang Kuo; Ming-Hsien Chien

doi:10.1016/j.bbamcr.2013.10.015

Vascular endothelial growth factor-C modulates proliferation and chemoresistance in acute myeloid leukemic cells through an endothelin-1-dependent induction of cyclooxygenase-2

Biochim Biophys Acta. 2014 Feb;1843(2):387-97. doi: 10.1016/j.bbamcr.2013.10.015. Epub 2013 Oct 31.

Authors

Kuo-Tai Hua¹, Wei-Jiunn Lee², Shun-Fa Yang³, Chi-Kuan Chen¹, Michael Hsiao⁴, Chia-Chi Ku⁵, Lin-Hung Wei⁶, Min-Liang Kuo⁷, Ming-Hsien Chien⁸

Affiliations

¹ Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.
² Department of Urology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
³ Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan; Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan.
⁴ The Genomics Research Center, Academia Sinica, Taipei, Taiwan.
⁵ Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
⁶ Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.
⁷ Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan; Graduate Institute of Biomedical Sciences, College of Life Science, National Taiwan University, Taipei, Taiwan.
⁸ Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. Electronic address: mhchien1976@gmail.com.

PMID: 24184161
DOI: 10.1016/j.bbamcr.2013.10.015

Abstract

High-level expression of vascular endothelial growth factor (VEGF)-C is associated with chemoresistance and adverse prognosis in acute myeloid leukemia (AML). Our previous study has found that VEGF-C induces cyclooxygenase-2 (COX-2) expression in AML cell lines and significant correlation of VEGF-C and COX-2 in bone marrow specimens. COX-2 has been reported to mediate the proliferation and drug resistance in several solid tumors. Herein, we demonstrated that the VEGF-C-induced proliferation of AML cells is effectively abolished by the depletion or inhibition of COX-2. The expression of endothelin-1 (ET-1) rapidly increased following treatment with VEGF-C. We found that ET-1 was also involved in the VEGF-C-mediated proliferation of AML cells, and that recombinant ET-1 induced COX-2 mRNA and protein expressions in AML cells. Treatment with the endothelin receptor A (ETRA) antagonist, BQ 123, or ET-1 shRNAs inhibited VEGF-C-induced COX-2 expression. Flow cytometry and immunoblotting revealed that VEGF-C induces S phase accumulation through the inhibition of p27 and the upregulation of cyclin E and cyclin-dependent kinase-2 expressions. The cell-cycle-related effects of VEGF-C were reversed by the depletion of COX-2 or ET-1. The depletion of COX-2 or ET-1 also suppressed VEGF-C-induced increases in the bcl-2/bax ratio and chemoresistance against etoposide and cytosine arabinoside in AML cells. We also demonstrated VEGF-C/ET-1/COX-2 axis-mediated chemoresistance in an AML xenograft mouse model. Our findings suggest that VEGF-C induces COX-2-mediated resistance to chemotherapy through the induction of ET-1 expression. Acting as a key regulator in the VEGF-C/COX-2 axis, ET-1 represents a potential target for ameliorating resistance to chemotherapy in AML patients.

Keywords: AML; CDK; CKIs; COX; Chemoresistance; Cyclooxygenase-2; ET-1; ETRA; ETRB; Endothelin-1; VEGF-C; acute myeloid leukemia; cyclin-dependent kinase; cyclin-dependent kinase inhibitors; cyclooxygenase; endothelin receptor A; endothelin receptor B; endothelin-1; vascular endothelial growth factor-C.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Cycle / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Cyclooxygenase 2 / biosynthesis*
Drug Resistance, Neoplasm* / drug effects
Endothelin-1 / metabolism*
Enzyme Induction / drug effects
Humans
Leukemia, Myeloid, Acute / enzymology*
Leukemia, Myeloid, Acute / pathology*
Male
Mice
Up-Regulation / drug effects
Vascular Endothelial Growth Factor C / metabolism*
Vascular Endothelial Growth Factor C / pharmacology

Substances

Endothelin-1
Vascular Endothelial Growth Factor C
Cyclooxygenase 2
PTGS2 protein, human