Proapoptotic and antitumor activities of adenovirus-mediated p202 gene transfer.
OBJECTIVE
p202, a mouse IFN-inducible protein, is a member of the 200-amino acid repeat family. Enforced p202 expression in stable cancer cell lines resulted in growth inhibition in vitro and tumor suppression in vivo. However, to study the immediate effect of p202 and test the potential efficacy of p202 treatment, an efficient gene delivery system for p202 is required. For these purposes, an adenoviral vector expressing the p202 gene (Ad-p202) was generated. We examined the effects of Ad-p202 infection on human breast cancer cells. Furthermore, we tested the efficacy of Ad-p202 treatment on breast and pancreatic cancer xenograft models.


RESULTS
We found that Ad-p202 infection induces growth inhibition and sensitizes the otherwise resistant cells to tumor necrosis factor alpha-induced apoptosis. In addition, we demonstrated for the first time that Ad-p202 infection induces apoptosis and that activation of caspases is required for the full apoptotic effect. More importantly, we showed the efficacy of Ad-p202 treatment on breast cancer xenograft models, and this antitumor effect correlated well with enhanced apoptosis in Ad-p202-treated tumors.


CONCLUSIONS
We conclude that Ad-p202 is a potent growth-inhibitory, proapoptotic, and tumor-suppressing agent. Ad-p202 may be further developed into an efficient therapeutic agent for human cancer gene therapy.
Ding
Yi
Y
Departments of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Wen
Yong
Y
Spohn
Bill
B
Wang
Li
L
Xia
Weiya
W
Kwong
Ka Yin
KY
Shao
Ruping
R
Li
Zheng
Z
Hortobagyi
Gabriel N
GN
Hung
Mien-Chie
MC
Yan
Duen-Hwa
DH
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D001943:Breast Neoplasms / Q000473:pathology / Q000517:prevention & control / Q000628:therapy*; D002352:Carrier Proteins / Q000235:genetics*; D020169:Caspases / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D010750:Phosphoproteins / Q000235:genetics*; D014162:Transfection; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D000071857:Tumor Suppressor p53-Binding Protein 1; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D002352:Carrier Proteins; C092537:Ifi202b protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D009687:Nuclear Proteins; D010750:Phosphoproteins; C498301:TP53BP1 protein, human; D014409:Tumor Necrosis Factor-alpha; D000071857:Tumor Suppressor p53-Binding Protein 1; D020169:Caspases