Antitumor effects of the antiparasitic agent ivermectin via inhibition of Yes-associated protein 1 expression in gastric cancer
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Sho Nambara1, Takaaki Masuda1, Miki Nishio2,3, Shotaro Kuramitsu1, Taro Tobo4, Yushi Ogawa5, Qingjiang Hu1, Tomohiro Iguchi6, Yousuke Kuroda1, Shuhei Ito1, Hidetoshi Eguchi1, Keishi Sugimachi1,6, Hiroshi Saeki7, Eiji Oki7, Yoshihiko Maehara7, Akira Suzuki2,3 and Koshi Mimori1
1Department of Surgery, Kyushu University Beppu Hospital, Beppu, Oita 874-0838, Japan
2Medical Institute of Bioregulation, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
3Division of Molecular and Cellular Biology, Kobe University Graduate School of Medicine, Chuo-Ku, Kobe, Hyogo 650-0017, Japan
4Department of Pathology, Kyushu University Beppu Hospital, Beppu, Oita 874-0838, Japan
5Digestive Disease Center, Showa University Northern Yokohama Hospital, Tsuzuki-Ku, Kanagawa 224-8503, Japan
6Department of Gastroenterological Surgery, National Kyushu Cancer Center, Fukuoka 811-1395, Japan
7Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
Koshi Mimori, email: email@example.com
Keywords: ivermectin; yes-associated protein 1 inhibitor; gastric cancer; antiproliferative effect; therapeutic target
Received: May 31, 2017 Accepted: November 03, 2017 Published: November 21, 2017
Yes-associated protein 1 (YAP1) acts as an oncogene through dephosphorylation and nuclear translocation, and nuclear accumulation of YAP1 is associated with poor prognosis in gastric cancer (GC). We previously identified ivermectin, an antiparasitic drug, as a YAP1 inhibitor. Here, we aimed to clarify whether ivermectin had antitumor effects on GC through inhibition of YAP1. First, we evaluated the antiproliferative effects of ivermectin on human GC cells using in vitro proliferation assays and a xenograft mouse model. YAP1-knockdown assays were performed to assess whether the sensitivity to ivermectin depended on YAP1 expression. Next, we explored the mechanism through which ivermectin regulated YAP1 expression or localization by immunoblotting and reverse transcription-quantitative polymerase chain reaction for YAP1 and the downstream gene CTGF. Finally, the clinical significance of YAP1 expression was examined using three independent GC datasets. We found that MKN1 GC cells were most sensitive to ivermectin, whereas MKN7 cells were most resistant. In MKN1 xenografts, ivermectin suppressed tumor growth, and the sensitivity of MKN1 cells to ivermectin was decreased by YAP1 knockdown. Ivermectin inhibited YAP1 nuclear expression and CTGF expression in MKN1 cells but not MKN7 cells. Moreover, ivermectin decreased YAP1 mRNA expression, thereby inhibiting nuclear accumulation of YAP1 in MKN1 cells. In survival analysis, low YAP1 mRNA expression was associated with a better prognosis in three independent GC datasets. In conclusion, we identified ivermectin as a potential antitumor agent and found a promising novel therapeutic strategy for inhibition of GC progression by blocking YAP1 expression.
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