Ivermectin Induces Cytostatic Autophagy by Blocking the PAK1/Akt Axis in Breast Cancer.
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.
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, P.R. China.
Qianhui
Q
Dou
Department of Gastrointestinal Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, P.R. China.
Hai-Ning
HN
Chen
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, P.R. China. Key Laboratory of Tropical Diseases and Translational Medicine of Ministry of Education & Department of Neurology, the Affiliated Hospital of Hainan Medical College, Haikou, China.
Kui
K
Wang
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, P.R. China.
Kefei
K
Yuan
Department of Biochemistry and Molecular Biology, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, P.R. China.
Yunlong
Y
Lei
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, P.R. China.
Kai
K
Li
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, P.R. China. Key Laboratory of Tropical Diseases and Translational Medicine of Ministry of Education & Department of Neurology, the Affiliated Hospital of Hainan Medical College, Haikou, China.
Jiang
J
Lan
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, P.R. China.
Yan
Y
Chen
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, P.R. China.
Zhao
Z
Huang
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, P.R. China.
Na
N
Xie
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, P.R. China.
Lu
L
Zhang
School of Medicine/Collaborative Innovation Center of Biotherapy, Nankai University, Tianjin, China.
Rong
R
Xiang
Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
Edouard C
EC
Nice
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, P.R. China.
Yuquan
Y
Wei
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, P.R. China. Key Laboratory of Tropical Diseases and Translational Medicine of Ministry of Education & Department of Neurology, the Affiliated Hospital of Hainan Medical College, Haikou, China. hcanhua@scu.edu.cn.
Canhua
C
Huang
D000818:Animals; D000977:Antiparasitic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001343:Autophagy; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007559:Ivermectin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D054462:p21-Activated Kinases / Q000235:genetics* / Q000378:metabolism
D000977:Antiparasitic Agents; D007559:Ivermectin; C515903:PAK1 protein, human; D054462:p21-Activated Kinases