Bradykinin promotes vascular endothelial growth factor expression and increases angiogenesis in human prostate cancer cells.
Prostate cancer is the most commonly diagnosed malignancy in men and shows a tendency for metastasis to distant organs. Angiogenesis is required for metastasis. Bradykinin (BK) is an inflammatory mediator involved in tumor growth and metastasis, but its role in vascular endothelial growth factor (VEGF) expression and angiogenesis in human prostate cancer remains unknown. The aim of this study was to examine whether BK promotes prostate cancer angiogenesis via VEGF expression. We found that exogenous BK increased VEGF expression in prostate cancer cells and further promoted tube formation in endothelial progenitor cells and human umbilical vein endothelial cells. Pretreatment of prostate cancer with B2 receptor antagonist or small interfering RNA (siRNA) reduced BK-mediated VEGF production. The Akt and mammalian target of rapamycin (mTOR) pathways were activated after BK treatment, and BK-induced VEGF expression was abolished by the specific inhibitor and siRNA of the Akt and mTOR cascades. BK also promoted nuclear factor-κB (NF-κB) and activator protein 1 (AP-1) activity. Importantly, BK knockdown reduced VEGF expression and abolished prostate cancer cell conditional medium-mediated angiogenesis. Taken together, these results indicate that BK operates through the B2 receptor, Akt, and mTOR, which in turn activate NF-κB and AP-1, activating VEGF expression and contributing to angiogenesis in human prostate cancer cells.
Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.
Hsin-Shan
HS
Yu
Department of Medicine, Mackay Medical College, New Taipei City, Taiwan.
Shih-Wei
SW
Wang
Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.
An-Chen
AC
Chang
Department of Urology, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Clinical Medicine, National Taiwan University, Taipei, Taiwan.
Huai-Ching
HC
Tai
Department of Medicine, Mackay Medical College, New Taipei City, Taiwan; Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan.
Hung-I
HI
Yeh
Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan; Department of Orthopedic Surgery, Taichung Veterans General Hospital, Taichung, Taiwan. Electronic address: yuminlin@gmail.com.
Yu-Min
YM
Lin
Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan; Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan; Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan. Electronic address: chtang@mail.cmu.edu.tw.
Chih-Hsin
CH
Tang
D001920:Bradykinin / Q000502:physiology*; D002478:Cells, Cultured; D015972:Gene Expression Regulation, Neoplastic; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008297:Male; D009389:Neovascularization, Pathologic / Q000473:pathology* / Q000503:physiopathology; D011471:Prostatic Neoplasms / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000819:agonists / Q000096:biosynthesis*
C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D001920:Bradykinin
Angiogenesis; Bradykinin; Prostate cancer; VEGF