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Ivermectin Induces Cytostatic Autophagy by Blocking the PAK1/Akt Axis in Breast Cancer

2016; American Association for Cancer Research; Volume: 76; Issue: 15 Linguagem: Inglês

10.1158/0008-5472.can-15-2887

1538-7445

Qianhui Dou, Hai‐Ning Chen, Kui Wang, Kefei Yuan, Yunlong Lei, Kai Li, Lan Jiang, Yan Chen, Zhao Huang, Na Xie, Lu Zhang, Rong Xiang, Edouard C. Nice, Yuquan Wei, Canhua Huang,

Histone Deacetylase Inhibitors Research

Breast cancer is the most common cancer among women worldwide, yet successful treatment remains a clinical challenge. Ivermectin, a broad-spectrum antiparasitic drug, has recently been characterized as a potential anticancer agent due to observed antitumor effects. However, the molecular mechanisms involved remain poorly understood. Here, we report a role for ivermectin in breast cancer suppression by activating cytostatic autophagy both in vitro and in vivo Mechanistically, ivermectin-induced autophagy in breast cancer cells is associated with decreased P21-activated kinase 1 (PAK1) expression via the ubiquitination-mediated degradation pathway. The inhibition of PAK1 decreases the phosphorylation level of Akt, resulting in the blockade of the Akt/mTOR signaling pathway. In breast cancer xenografts, the ivermectin-induced cytostatic autophagy leads to suppression of tumor growth. Together, our results provide a molecular basis for the use of ivermectin to inhibit the proliferation of breast cancer cells and indicate that ivermectin is a potential option for the treatment of breast cancer. Cancer Res; 76(15); 4457-69. ©2016 AACR.