Abstract
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.
Highlights
Breast cancer is the most frequent cancer among women and ranks as the fifth leading cause of cancer-related death worldwide with more than 1.67 million people diagnosed annually, with over 522,000 deaths per year [1]
To determine whether ivermectin induces apoptosis in breast cancer cells, we evaluated the apoptotic rate using both TUNEL and flow cytometry assays
Our data revealed that ivermectin suppressed Akt/mTOR signaling by promoting ubiquitination degradation of PAK1, and thereby activated cytostatic autophagy, leading to inhibition of tumor growth in breast cancer cells
Summary
Breast cancer is the most frequent cancer among women and ranks as the fifth leading cause of cancer-related death worldwide with more than 1.67 million people diagnosed annually, with over 522,000 deaths per year [1]. In combination with radiotherapy when necessary, affords curative treatment for early or local disease, approximately 70% patients with advanced breast cancer require cytotoxic chemotherapy, endocrine therapy, biologic therapy, or combinations of these [2]. Despite the diverse strategies that have been proposed to improve the current situation, the prognosis for patients with advanced breast cancer still remains. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).
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