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

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 ubiquitinationmediated 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. Ó2016 AACR.

Shear force-based genetic screen reveals negative regulators of cell adhesion and protrusive activity

“…Thymosin β4, a human member of the Actobindin family, has been reported to play the role of both an oncogene and tumor suppressor under different contexts (82,83). SepA shares homology with human MSTs and PAKs, known tumor supressors that are currently being investigated as therapeutic targets (84,85). Human Tenascin-C is reported to play a role in the progression and metastasis of breast cancer and as a potential target (86,87).…”

Discovery of a small molecule targeting ULK1-modulated cell death of triple negative breast cancer in vitro and in vivo

“…25 Ivermectin, a broad-spectrum anti-parasitic drug, has been found to induce cytostatic autophagy by blocking the PAK1/Akt axis in breast cancer. 26 However, these small molecules either have no specific targets or possess some other complex mechanisms that are not directly regulated by autophagy-related (ATG) proteins. Unlike the above-mentioned molecules, LYN-1604 can induce ATG5-dependent autophagy in TNBC cells by targeting the ULK complex, which may provide an autophagy-modulating agent for potential TNBC therapeutics.…”

Lycorine Promotes Autophagy and Apoptosis via TCRP1/Akt/mTOR Axis Inactivation in Human Hepatocellular Carcinoma

“…The Akt/mTOR pathway that is very frequently dysregulated in the pathogenesis of human cancers is a major pathway accounting for autophagy, proliferation, and apoptosis of cancer cells (26,49). Therefore, it is a potential pathway and target for intervention in cancer prevention and treatment.…”

“…Transmission electron microscopy was performed as described previously (26). In brief, the cells were treated with lycorine at 40 mmol/L for 48 hours and fixed with 4% glutaraldehyde.…”