Synergistic anti-tumor effect of paclitaxel with CRM197, an inhibitor of HB-EGF, in ovarian cancer.
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 anti-tumor effects of paclitaxel, as an anti-cancer agent, and CRM197, as a specific inhibitor off HB-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 paclitaxel-evoked 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 inhibitory 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.
Yagi
Hiroshi
H
Department of Obstetrics and Gynecology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Yotsumoto
Fusanori
F
Sonoda
Kenzo
K
Kuroki
Masahide
M
Mekada
Eisuke
E
Miyamoto
Shingo
S
D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001426:Bacterial Proteins / Q000627:therapeutic use*; D002470:Cell Survival / Q000187:drug effects; D017931:DNA Primers; D004167:Diphtheria Toxin / Q000627:therapeutic use*; D005260:Female; D006494:Heparin Antagonists; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017239:Paclitaxel / Q000627:therapeutic use*; D010957:Plasmids; D016133:Polymerase Chain Reaction; D012334:RNA, Neoplasm / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000235:genetics; D014162:Transfection
D000972:Antineoplastic Agents, Phytogenic; D001426:Bacterial Proteins; D017931:DNA Primers; D004167:Diphtheria Toxin; C587883:HBEGF protein, human; C587884:Hbegf protein, mouse; D006494:Heparin Antagonists; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D012334:RNA, Neoplasm; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; C028581:CRM197 (non-toxic variant of diphtheria toxin); D020929:Mitogen-Activated Protein Kinase Kinases; D017239:Paclitaxel