title: Vascular endothelial growth factor-C modulates proliferation and chemoresistance in acute myeloid leukemic cells through an endothelin-1-dependent induction of cyclooxygenase-2.
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.
authors.affiliation: Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Kuo-Tai
authors.initials: KT
authors.lastname: Hua
authors.affiliation: Department of Urology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
authors.forename: Wei-Jiunn
authors.initials: WJ
authors.lastname: Lee
authors.affiliation: Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan; Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan.
authors.forename: Shun-Fa
authors.initials: SF
authors.lastname: Yang
authors.affiliation: Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Chi-Kuan
authors.initials: CK
authors.lastname: Chen
authors.affiliation: The Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Michael
authors.initials: M
authors.lastname: Hsiao
authors.affiliation: Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
authors.forename: Chia-Chi
authors.initials: CC
authors.lastname: Ku
authors.affiliation: Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Lin-Hung
authors.initials: LH
authors.lastname: Wei
authors.affiliation: 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.
authors.forename: Min-Liang
authors.initials: ML
authors.lastname: Kuo
authors.affiliation: 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.
authors.forename: Ming-Hsien
authors.initials: MH
authors.lastname: Chien
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D019332:Endothelin-1 / Q000378:metabolism*; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology* / Q000473:pathology*; D008297:Male; D051379:Mice; D015854:Up-Regulation / Q000187:drug effects; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D019332:Endothelin-1; D042582:Vascular Endothelial Growth Factor C; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human
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