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Tumor resistance to oxidative stress: Association with ras oncogene expression and reversal by lovastatin, an inhibitor of p21 ras isoprenylation
Author(s) -
Miller Alexandra C.,
Samid Dvorit
Publication year - 1995
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.2910600220
Subject(s) - lovastatin , glutathione , oncogene , glutathione peroxidase , biology , superoxide dismutase , oxidative stress , glutathione reductase , microbiology and biotechnology , cancer research , biochemistry , cell , enzyme , cell cycle , cholesterol
The ras oncogene family has been implicated in tumor resistance to ionizing radiotherapy. Using the gene‐transfer model, we show here that ras expression may also affect cell responses to chemical inducers of oxidative stress. Studies involving human osteosarcoma subclones, which vary in their levels of EJ ras expression, revealed a tight correlation between the amounts of ras ‐encoded mRNA and p21 produced, and the degree of resistance to doxorubicin or hydrogen peroxide. Differences in response could not be explained by increased activity of anti‐oxidant enzymes such as superoxide dismutase, glutathione reductase, glutathione S‐transferase or glutathione peroxidase. Moreover, there were no significant differences in glutathione levels. Although the resistant cells had elevated levels of gamma‐glutamyl‐transferase mRNA indicative of an increased rate of glutathione turnover, this elevation was not specific for ras ‐transfected cell lines. Lovastatin, an inhibitor of protein isoprenylation critical for p21 ras membrane association and function, restored the sensitivity of ras ‐transformed cells to doxorubicin and hydrogen peroxide. The data indicate that pharmacological agents affecting ras expression may enhance responses of some human tumors to free‐radical‐mediated chemotherapies. © 1995 Wiley‐Liss, Inc.