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Antitumor effects of the antiparasitic agent ivermectin via inhibition of Yes-associated protein 1 expression in gastric cancer

2017; Impact Journals LLC; Volume: 8; Issue: 64 Linguagem: Inglês

10.18632/oncotarget.22587

1949-2553

Sho Nambara, Takaaki Masuda, Miki Nishio, Shotaro Kuramitsu, Taro Tobo, Yushi Ogawa, Qingjiang Hu, Tomohiro Iguchi, Yousuke Kuroda, Shuhei Ito, Hidetoshi Eguchi, K Sugimachi, Hiroshi Saeki, Eiji Oki, Yoshihiko Maehara, Akira Suzuki, Koshi Mimori,

Cancer Mechanisms and Therapy

// Sho Nambara 1 , Takaaki Masuda 1 , Miki Nishio 2, 3 , Shotaro Kuramitsu 1 , Taro Tobo 4 , Yushi Ogawa 5 , Qingjiang Hu 1 , Tomohiro Iguchi 6 , Yousuke Kuroda 1 , Shuhei Ito 1 , Hidetoshi Eguchi 1 , Keishi Sugimachi 1, 6 , Hiroshi Saeki 7 , Eiji Oki 7 , Yoshihiko Maehara 7 , Akira Suzuki 2, 3 and Koshi Mimori 1 1 Department of Surgery, Kyushu University Beppu Hospital, Beppu, Oita 874-0838, Japan 2 Medical Institute of Bioregulation, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan 3 Division of Molecular and Cellular Biology, Kobe University Graduate School of Medicine, Chuo-Ku, Kobe, Hyogo 650-0017, Japan 4 Department of Pathology, Kyushu University Beppu Hospital, Beppu, Oita 874-0838, Japan 5 Digestive Disease Center, Showa University Northern Yokohama Hospital, Tsuzuki-Ku, Kanagawa 224-8503, Japan 6 Department of Gastroenterological Surgery, National Kyushu Cancer Center, Fukuoka 811-1395, Japan 7 Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan Correspondence to: Koshi Mimori, email: kmimori@beppu.kyushu-u.ac.jp 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 ABSTRACT 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.