RNA interference-mediated knockdown of p21(WAF1) enhances anti-tumor cell activity of oncolytic adenoviruses.
The ability of oncolytic adenoviruses to replicate in and lyse cancer cells offers a potential therapeutic approach. However, selectivity and efficacy of adenovirus replication need to be improved. In this study, we present that loss of p21(WAF1) promotes adenovirus replication and more effective cell killing. To test our hypothesis, we took HCT116 colon cancer cell lines carrying deletions of either p21(WAF1) or p53, and infected these cell lines with wild-type adenovirus (WtD) or the oncolytic adenoviruses, ONYX-015 and Delta-24. We found that WtD, ONYX-015 and Delta-24 induced stronger cytopathic effects in HCT116 p21-/- cells compared with HCT116-WT cells. This was accompanied by increased virus production. siRNA-mediated knockdown of p21(WAF1), and similarly of p27(KIP1), in HCT116-WT cells also enhanced replication of and cell killing by these viruses. Furthermore, we found that TE7, an esophageal carcinoma cell line, also showed a strong cell-killing effect and virus production when p21(WAF1) expression was suppressed by RNA interference before adenoviruses infection. Also, H1299 and DU-145 cells transfected with p21(WAF1) siRNA showed higher virus production after ONYX-015 and Delta-24 infections. These observations suggest that p21(WAF1) plays a role in mediating replication of oncolytic viruses with potential implications for adenoviral therapy of cancer.
Shiina
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M
Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Helen Diller Family Comprehensive Cancer Center, University of California-San Francisco, San Francisco, CA 94143-0128, USA.
Lacher
M D
MD
Christian
C
C
Korn
W M
WM
D000256:Adenoviridae / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D002470:Cell Survival; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics*; D055785:Gene Knockdown Techniques; D045325:HCT116 Cells; D006801:Humans; D015151:Immunoblotting; D050504:Oncolytic Viruses / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D034622:RNA Interference / Q000502:physiology*
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21