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Protease inhibitor-induced stabilization of p21(waf1/cip1) and cell-cycle arrest in chemical carcinogen-exposed mammary and lung cells

  1. Author:
    Khan, Q. A.
    Dipple, A.
    Anderson, L. M.

  2. Author Address

    NCI, Mol Pharmacol Lab, Bldg 37, Bethesda, MD 20892 USA. NCI, Cellular Pathogenesis Sect, Comparat Carcinogenesis Lab, Frederick, MD 21701 USA. Adv Biosci Labs, Basic Res Program, Frederick, MD USA. Khan QA NCI, Mol Pharmacol Lab, Bldg 37, Bethesda, MD 20892 USA.
    1. Year: 2002
  2. Journal: Molecular Carcinogenesis
    1. 33
    2. 1
    3. Pages: 1-8
  4. Type of Article: Article
  1. 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 11 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. Published 2002 Wiley-Liss, Inc.(dagger).

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