Blockage of autophagy pathway enhances Salmonella tumor-targeting

// Binghong Liu 1, 2, 3, * , Yanan Jiang 1, 2, * , Tiangeng Dong 4 , Ming Zhao 5, 7 , Jianfu Wu 1, 2 , Lihui Li 1 , Yiwei Chu 2 , Shangyang She 3 , Hu Zhao 6 , Robert M. Hoffman 5, 7 , Lijun Jia 1 1 Cancer Institute, Fudan University Shanghai Cancer Center, Collaborative Innovation Center of Cancer Medicine, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China 2 Department of Immunology, Shanghai Medical College, Fudan University, Shanghai 200032, China 3 Department of Clinical Laboratory, Children’s Hospital, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning 530003, China 4 Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China 5 Department of Surgery, University of California, San Diego, California 92103, USA 6 Department of Clinical Laboratory, Huadong Hospital, Shanghai Key Laboratory of Clinical Geriatric Medicine, Research Center on Aging and Medicine, Fudan University, Shanghai 200040, China 7 AntiCancer, Inc., San Diego, California 92111, USA * These authors contributed equally to this work Correspondence to: Lijun Jia, e-mail: ljjia@fudan.edu.cn Robert M. Hoffman, e-mail: all@anticancer.com Hu Zhao, e-mail: hubertzhao@163.com Keywords: autophagy, Salmonella typhimurium A1-R, bacteria, cancer, apoptosis Received: October 20, 2015      Accepted: February 23, 2016      Published: March 22, 2016 ABSTRACT 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.