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Research ArticleArticle

Suppression of hREV1 Expression Reduces the Rate at Which Human Ovarian Carcinoma Cells Acquire Resistance to Cisplatin

Tsuyoshi Okuda, Xinjian Lin, Julie Trang and Stephen B. Howell
Molecular Pharmacology June 2005, 67 (6) 1852-1860; DOI: https://doi.org/10.1124/mol.104.010579
Tsuyoshi Okuda
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Xinjian Lin
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Julie Trang
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Stephen B. Howell
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Abstract

Replicative bypass of many DNA adducts is dependent on the interaction of hREV1 with DNA polymerase ζ and potentially with members of the Y family of DNA polymerases. To examine the role of hREV1 in the development of cisplatin (DDP) resistance, a subline (2008-shREV1-3.3) of the ovarian carcinoma cell line 2008 was isolated in which stable expression of a short hairpin RNA suppressed hREV1 expression to 20% and reduced hREV1 protein level to 43% of that found in the parental cells. The 2008-shREV1-3.3 cells were 1.5-fold more sensitive to the cytotoxic effect of DDP but less sensitive to the mutagenic effect of DDP as evidenced by a 2.6- or 2.7-fold reduction in the ability to induce clones highly resistant to 6-thioguanine or DDP itself, respectively, in the surviving population. Reduction of hREV1 did not alter the initial rate of DDP adduct removal from DNA but did impair both spontaneous and DDP-induced extra-chromosomal homologous recombination, as measured by the recombination-sensitive reporter vector pBHRF. DDP induced an increase in hREV1 protein level. DDP resistance at the population level evolved 2.8-fold more slowly in the 2008-shREV1-3.3 cells than in the parental cells during repeated cycles of drug exposure. The results indicate that hREV1 functions to enhance both cell survival and the generation of drug-resistant variants in the surviving population. DDP up-regulates hREV1, suggesting that it may enhance its own mutagenicity. Most importantly, hREV1 controls the rate of emergence of resistance to DDP at the population level. Thus, hREV1 is an important contributor to DDP-induced genomic instability and the subsequent emergence of resistance.

  • Received December 22, 2004.
  • Accepted March 8, 2005.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 67 (6)
Molecular Pharmacology
Vol. 67, Issue 6
1 Jun 2005
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Research ArticleArticle

Suppression of hREV1 Expression Reduces the Rate at Which Human Ovarian Carcinoma Cells Acquire Resistance to Cisplatin

Tsuyoshi Okuda, Xinjian Lin, Julie Trang and Stephen B. Howell
Molecular Pharmacology June 1, 2005, 67 (6) 1852-1860; DOI: https://doi.org/10.1124/mol.104.010579

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Research ArticleArticle

Suppression of hREV1 Expression Reduces the Rate at Which Human Ovarian Carcinoma Cells Acquire Resistance to Cisplatin

Tsuyoshi Okuda, Xinjian Lin, Julie Trang and Stephen B. Howell
Molecular Pharmacology June 1, 2005, 67 (6) 1852-1860; DOI: https://doi.org/10.1124/mol.104.010579
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