title: Protease inhibitor-induced stabilization of p21(waf1/cip1) and cell-cycle arrest in chemical carcinogen-exposed mammary and lung cells.
abstract: In previous studies, we have shown that human breast and lung carcinoma cells and mouse nontransformed type II lung cells fail to undergo cell-cycle arrest in G(1) phase in response to treatment with hydrocarbon carcinogens but rather accumulate in the S phase with damaged DNA. This situation may lead to replication of DNA on a damaged template and enhance frequency of mutations. The mechanism of this G(1) arrest failure was examined. Western immunoblot analyses of MCF7 human mammary cancer cells exposed to actinomycin D (used as a positive control for G(1) cell-cycle arrest) or hydrocarbon carcinogens revealed that while all of these chemicals caused an increase in p53, only trace levels of p21(waf1/cip1) protein were observed in the hydrocarbon carcinogen-treated samples. Similarly, in murine lung E10 type II cells, p53 but not p21(waf1/cip1) protein increased in response to benzo[a]pyrene dihydrodiol epoxide. Treatment of either MCF7 mammary or E10 lung cells with the protease inhibitor calpain I resulted in increased levels of p21(waf1/cip1) protein and enhancement of arrest of the cells in early phases of the cell cycle (G(1) and early S phase). The results suggest that failure of cell-cycle arrest in carcinogen-treated mammary and lung cells is related to increased protease-mediated degradation of p21(waf1/cip1) and/or related regulatory proteins.
authors.affiliation: Cellular Pathogenesis Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at Frederick, Frederick, Maryland, USA.
authors.forename: Qasim A
authors.initials: QA
authors.lastname: Khan
authors.forename: Anthony
authors.initials: A
authors.lastname: Dipple
authors.forename: Lucy M
authors.initials: LM
authors.lastname: Anderson
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism*; D002273:Carcinogens / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects*; D002911:Chrysenes / Q000494:pharmacology; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D003609:Dactinomycin / Q000494:pharmacology; D004847:Epithelial Cells / Q000378:metabolism*; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006023:Glycoproteins / Q000494:pharmacology; D006801:Humans; D008168:Lung / Q000378:metabolism*; D051379:Mice; D015739:Nocodazole / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D002273:Carcinogens; C493957:Cdkn1a protein, mouse; D002911:Chrysenes; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D015853:Cysteine Proteinase Inhibitors; D006023:Glycoproteins; D016159:Tumor Suppressor Protein p53; C039304:calpain inhibitors; C089231:benzo(g)chrysene-11,12-dihydrodiol-13,14-epoxide; D003609:Dactinomycin; D015739:Nocodazole