Protease inhibitor–induced stabilization of p21waf1/cip1 and cell-cycle arrest in chemical carcinogen–exposed mammary and lung cells

✍ Scribed by Qasim A. Khan; Anthony Dipple; Lucy M. Anderson

• Publisher: John Wiley and Sons
• Year: 2002
• Tongue: English
• Weight: 304 KB
• Volume: 33
• Category: Article
• ISSN: 0899-1987
• DOI: 10.1002/mc.10013

✦ Synopsis

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. Published 2002 Wiley‐Liss, Inc.