Suppression of cancer cell growth by adenovirus expressing p21(WAF1/CIP1) deficient in PCNA interaction.
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.
Prabhu
N S
NS
Howard Hughes Medical Institute, Laboratory of Molecular Oncology, Chicago, Illinois, USA.
Blagosklonny
M V
MV
Zeng
Y X
YX
Wu
G S
GS
Waldman
T
T
El-Deiry
W S
WS
D000256:Adenoviridae / Q000235:genetics*; D017209:Apoptosis; D042846:CDC2-CDC28 Kinases; D002455:Cell Division; D003110:Colonic Neoplasms / Q000473:pathology* / Q000628:therapy; D051357:Cyclin-Dependent Kinase 2; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000032:analysis; D016213:Cyclins / Q000172:deficiency / Q000502:physiology*; D006801:Humans; D009154:Mutation; D009856:Oncogene Proteins, Viral / Q000502:physiology; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis*; D017346:Protein Serine-Threonine Kinases / Q000032:analysis; D012097:Repressor Proteins; D014162:Transfection; D014407:Tumor Cells, Cultured
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D018809:Proliferating Cell Nuclear Antigen; D012097:Repressor Proteins; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases