Blockage of autophagy pathway enhances Salmonella tumor-targeting
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Binghong Liu1,2,3,*, Yanan Jiang1,2,*, Tiangeng Dong4, Ming Zhao5,7, Jianfu Wu1,2, Lihui Li1, Yiwei Chu2, Shangyang She3, Hu Zhao6, Robert M. Hoffman5,7, Lijun Jia1
1Cancer Institute, Fudan University Shanghai Cancer Center, Collaborative Innovation Center of Cancer Medicine, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
2Department of Immunology, Shanghai Medical College, Fudan University, Shanghai 200032, China
3Department of Clinical Laboratory, Children’s Hospital, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning 530003, China
4Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
5Department of Surgery, University of California, San Diego, California 92103, USA
6Department of Clinical Laboratory, Huadong Hospital, Shanghai Key Laboratory of Clinical Geriatric Medicine, Research Center on Aging and Medicine, Fudan University, Shanghai 200040, China
7AntiCancer, Inc., San Diego, California 92111, USA
*These authors contributed equally to this work
Lijun Jia, e-mail: [email protected]
Robert M. Hoffman, e-mail: [email protected]
Hu Zhao, e-mail: [email protected]
Keywords: autophagy, Salmonella typhimurium A1-R, bacteria, cancer, apoptosis
Received: October 20, 2015 Accepted: February 23, 2016 Published: March 22, 2016
Previous studies have shown that strains of Salmonella typhimurium specifically target tumors in mouse models of cancer. In this study, we report that tumor-targeting Salmonella typhimurium A1-R (A1-R) or VNP20009 induced autophagy in human cancer cells, which serves as a defense response. Functionally, by knockdown of essential autophagy genes Atg5 or Beclin1 in bacteria-infected cancer cells, the autophagy pathway was blocked, which led to a significant increase of intracellular bacteria multiplication in cancer cells. Genetic inactivation of the autophagy pathway enhanced A1-R or VNP20009-mediated cancer cell killing by increasing apoptotic activity. We also demonstrate that the combination of pharmacological autophagy inhibitors chloroquine (CQ) or bafilomycin A1 (Baf A1) with tumor-targeting A1-R or VNP20009 significantly enhanced cancer-cell killing compared with Salmonella infection alone. These findings provide a proof-of-concept of combining autophagy inhibitors and tumor-targeting Salmonella to enhance cancer-cell killing.
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