Potent antitumor efficacy of ST13 for colorectal cancer mediated by oncolytic adenovirus via mitochondrial apoptotic cell death.
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.
Yang
Min
M
Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Cao
Xin
X
Yu
Ming Can
MC
Gu
Jin Fa
JF
Shen
Zong Hou
ZH
Ding
Miao
M
Yu
De Bing
DB
Zheng
Shu
S
Liu
Xin yuan
Xy
D000256:Adenoviridae / Q000235:genetics* / Q000502:physiology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000628:therapy*; D045304:Cytochromes c / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D019254:Genes, bcl-2 / Q000235:genetics; D015316:Genetic Therapy; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000473:pathology*; D050130:Oncolytic Virotherapy; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D018832:Molecular Chaperones
D002352:Carrier Proteins; D061945:Caspase Inhibitors; D020169:Caspases; D045304:Cytochromes c; D018840:HSP70 Heat-Shock Proteins; D025521:Tumor Suppressor Proteins; C101119:ST13 protein, human; D018832:Molecular Chaperones