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

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.

KIF15 Expression in Tumor-associated Monocytes Is a Prognostic Biomarker in Hepatocellular Carcinoma

“…. Immunohistochemical analysis of KIF15 expression was performed with formalin-fixed paraffinembedded surgical sections (FFPE) obtained from patients with HCC, or a HCC cell line (HepG2) or healthy donor PBMC, as previously described (21,26). Primary rabbit polyclonal antibody against KIF15 (ab90735; Abcam) was used at a dilution of 1:200.…”

Ivermectin, a potential anticancer drug derived from an antiparasitic drug

“…In the past year, more than one million patients with gastric cancer have been diagnosed worldwide [ 38 ]. Nambara’s study showed that IVM could significantly inhibit the proliferation of gastric cancer cells in vivo and in vitro and that the inhibitory effect of IVM depended on the expression of Yes-associated protein 1(YAP1)[ 39 ]. The gastric cancer cell lines MKN1 and SH-10-TC have higher YAP1 expression than MKN7 and MKN28 cells, so MKN1 and SH-10-TC cells are sensitive to IVM, while MKN7 and MKN28 are not sensitive to IVM.YAP1 plays an oncogenic role in tumorigenesis, indicating the possibility of the use of IVM as a YAP1 inhibitor for cancer treatment [ 40 ].…”

Targeting the Hippo Pathway Is a New Potential Therapeutic Modality for Malignant Mesothelioma

“…Notably, however, the administration of dasatinib as a single-agent was not effective as a second-line treatment for MM during a recent phase II trial [ 16 ]; likewise, administration of dasatinib as a neoadjuvant treatment was not shown to confer any benefit to patients with MPM. In contrast, a recent study reported the ability of the anti-parasitic agent ivermectin to inhibit YAP1, and thereby exert significant effects on gastric cancer [ 134 ], hepatocellular carcinoma, and MM cells [ 130 ].…”