期刊
INTERNATIONAL JOURNAL OF CANCER
卷 124, 期 6, 页码 1429-1439出版社
WILEY
DOI: 10.1002/ijc.24031
关键词
CRM197; HB-EGF; paclitaxel; EGFR; ovarian cancer
类别
资金
- Scientific Research on Priority Areas [19591947]
- Fukuoka University Research Foundation
- Ministry of Education, Culture, Sports, Science and Technology
- Grants-in-Aid for Scientific Research [19591947] Funding Source: KAKEN
Heparin-binding EGF-like growth factor (HB-EGF) plays a pivotal role in tumor growth and clinical outcomes in patients with ovarian cancer, leading to the validation of HB-EGF as a target for ovarian cancer therapy. In this study, we investigated the antitumor effects of paclitaxel, as an anti-cancer agent, and CRM197, as a specific inhibitor off HR-EGF, in ovarian cancer. Paclitaxel induced transient ERK activation and sustained activation of JNK and p38 MAPK through the ectodomain shedding of HB-EGF in SKOV3 cells. In addition, the overexpression of HB-EGF in paclitaxel-treated SKOV3 cells resulted in modulation of paclitaxelevoked MAPK signaling, including marked activation of ERK and Akt, and minimized activation of JNK and p38 MAPK, indicating that HB-EGF is involved in drug sensitivity through the balance of anti-apoptotic and pro-apoptotic signals induced by paclitaxel. The combination of paclitaxel with CRM197 had an inhibitor effect on cell proliferation and enhanced apoptosis via the inhibition of ERK and Akt activation and the stimulation of p38 and JNK activation. More prominently, the administration of paclitaxel with CRM197 resulted in synergistic anti-tumor effects in SKOV3 cells and in SKOV3 cells overexpressing HB-EGF in xenografted mice. Accordingly, inhibitory agents against HB-EGF, such as CRM197, represent possible chemotherapeutic and chemosensitizing agents for ovarian cancer. (C) 2008 Wiley-Liss, Inc.
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