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  • Title: Suppression of cancer cell growth by adenovirus expressing p21(WAF1/CIP1) deficient in PCNA interaction.
    Author: Prabhu NS, Blagosklonny MV, Zeng YX, Wu GS, Waldman T, El-Deiry WS.
    Journal: Clin Cancer Res; 1996 Jul; 2(7):1221-9. PubMed ID: 9816291.
    Abstract:
    p53 tumor suppression is deficient in the majority of human cancers. Efforts to understand this pathway have identified cyclin-dependent kinase (CDK) inhibitors and suggested a potential for their replacement in human cancer. In the present studies, expression of a C-terminal deletion mutant of the human p21(WAF1/CIP1) CDK inhibitor completely suppressed the growth of colon cancer cells, whereas full-length p21 only partially suppressed growth. We prepared a replication-deficient adenoviral recombinant which expresses the p21 C-terminal mutant (Ad-WAF1-341) and compared its tumor suppressive abilities with Ad-p53 and Ad-LacZ. Ad-WAF1-341- and Ad-p53-infected cancer cells, but not Ad-LacZ-infected cancer cells, expressed a nuclear protein recognized by anti-p21 antibody and were deficient in cell cycle progression. The exogenous p21 mutant interacted with CDK2 but not proliferating cell nuclear antigen following infection of p21-/- cancer cells. Ad-WAF1-341 was more potent than Ad-p53 in inhibiting DNA synthesis in human papillomavirus 16 E6-expressing cancer cells. Most importantly, the Ad-WAF1-341-infected E6-expressing cells died, whereas most of the Ad-p53-infected cells continued to proliferate. Endonucleolytic cleavage of DNA was observed in Ad-WAF1-341-infected cancer cells. These observations suggest that Ad-WAF1-341 should be evaluated in the treatment of human papillomavirus-associated neoplasia and other neoplasias resistant to p53.
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