Role of p53 and p21waf1/cip1 in senescence-like terminal proliferation arrest induced in human tumor cells by chemotherapeutic drugs.
Exposure of human tumor cell lines to moderate doses of anticancer agents induces terminal proliferation arrest accompanied by morphologic and enzymatic changes that resemble senescence of normal cells. We have investigated the role of p53 and p21waf1/cip1 in the induction of this response in drug-treated tumor cells. Doxorubicin treatment induced the senescence-like phenotype (SLP) and its associated terminal growth arrest in wild-type HCT116 colon carcinoma cells; this response was strongly decreased but not abolished in HCT116 lines with homozygous knockout of p53 or p21. Transduction of HT1080 fibrosarcoma cells with a genetic inhibitor of p53 also decreased the induction of SLP and increased drug-induced mitotic cell death. To determine if drug-stimulated p21 expression was responsible for senescence-like growth arrest, we have expressed different levels of p21 from an inducible promoter. While high-level overexpression of p21 was sufficient to induce SLP in HT1080 cells, the levels of p21 expressed in doxorubicin-treated cells could account for only a fraction of doxorubicin-induced SLP. Our results indicate that p53 and p21 act as positive regulators of senescence-like terminal proliferation arrest, but their function is neither sufficient nor absolutely required for this treatment response in tumor cells.
Chang
B D
BD
Department of Molecular Genetics, University of Illinois at Chicago, Chicago, Illinois, IL 60607-7170, USA.
Xuan
Y
Y
Broude
E V
EV
Zhu
H
H
Schott
B
B
Fang
J
J
Roninson
I B
IB
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002277:Carcinoma / Q000188:drug therapy / Q000473:pathology; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D016922:Cellular Senescence / Q000187:drug effects* / Q000235:genetics; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D005354:Fibrosarcoma / Q000188:drug therapy / Q000473:pathology; D005456:Fluorescent Dyes / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009930:Organic Chemicals; D012045:Regulatory Sequences, Nucleic Acid; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D001616:beta-Galactosidase / Q000187:drug effects / Q000378:metabolism
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D005456:Fluorescent Dyes; D009930:Organic Chemicals; C067882:PKH2-GL; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; D001616:beta-Galactosidase