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Human Gene Therapy
Potent Antitumor Efficacy of ST13 for Colorectal Cancer Mediated by Oncolytic Adenovirus via Mitochondrial Apoptotic Cell Death
To cite this paper:
Min Yang, Xin Cao, Ming Can Yu, Jin Fa Gu, Zong Hou Shen, Miao Ding, De Bing Yu, Shu Zheng, Xin Yuan Liu.
Human Gene Therapy.
April 1, 2008,
19(4): 343-353.
doi:10.1089/hum.2007.0137.
Min Yang Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032, China. Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China. Xin Cao Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China. Ming Can Yu Kathleen B. and Mason I. Lowance Center for Human Immunology, Emory University, Atlanta, GA 30322. Jin Fa Gu Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China. Zong Hou Shen Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032, China. Miao Ding Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China. De Bing Yu Xinyuan Institute of Medicine and Biotechnology, Zhejiang Sci-Tech University, Hangzhou 100051, China. Shu Zheng Cancer Institute, Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310009, China. Xin Yuan Liu Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China. Xinyuan Institute of Medicine and Biotechnology, Zhejiang Sci-Tech University, Hangzhou 100051, China. ST13 is a cofactor of heat shock protein 70 (Hsp70). To date, all data since the discovery of ST13 in 1993 until more recent studies in 2007 have proved that ST13 is downregulated in tumors and it was proposed to be a tumor suppressor gene, but no work reported its antitumor effect and apoptotic mechanism. In the work described in this paper, ST13 was inserted into ZD55, an oncolytic adenovirus with the E1B 55-kDa gene deleted, to form ZD55-ST13, which exerts an excellent antitumor effect in vitro and in an animal model of colorectal carcinoma SW620 xenograft. ZD55-ST13 inhibited tumor cells 100-fold more than Ad-ST13 and ZD55-EGFP in vitro. However, ZD55-ST13 showed no damage of normal fibroblast MRC5 cells. In exploring the mechanism of ZD55-ST13 in tumor cell killing, we found that ZD55-ST13-infected SW620 cells formed apoptotic bodies and presented obvious apoptosis phenomena. ZD55-ST13 induced the upregulation of Hsp70, the downregulation of antiapoptotic gene Bcl-2, and the release of cytochrome c. Cytochrome c triggered apoptosis by activating caspase-9 and caspase-3, which cleave the enzyme poly(ADP-ribose) polymerase in ZD55-ST13-infected SW620 cells. In summary, overexpressed ST13 as mediated by oncolytic adenovirus could exert potent antitumor activity via the intrinsic apoptotic pathway and has the potential to become a novel therapeutic for colorectal cancer gene therapy. 
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