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ISG15 as a novel tumor biomarker for drug sensitivity.

Publication ,  Journal Article
Desai, SD; Wood, LM; Tsai, Y-C; Hsieh, T-S; Marks, JR; Scott, GL; Giovanella, BC; Liu, LF
Published in: Mol Cancer Ther
June 2008

Tumor cells are known to exhibit highly varied sensitivity to camptothecins (CPT; e.g., irinotecan and topotecan). However, the factors that determine CPT sensitivity/resistance are largely unknown. Recent studies have shown that the ubiquitin-like protein, IFN-stimulated gene 15 (ISG15), which is highly elevated in many human cancers and tumor cell lines, antagonizes the ubiquitin/proteasome pathway. In the present study, we show that ISG15 is a determinant for CPT sensitivity/resistance possibly through its effect on proteasome-mediated repair of topoisomerase I (TOP1)-DNA covalent complexes. First, short hairpin RNA-mediated knockdown of either ISG15 or UbcH8 (major E2 for ISG15) in breast cancer ZR-75-1 cells decreased CPT sensitivity, suggesting that ISG15 overexpression in tumors could be a factor affecting intrinsic CPT sensitivity in tumor cells. Second, the level of ISG15 was found to be significantly reduced in several tumor cells selected for resistance to CPT, suggesting that altered ISG15 regulation could be a significant determinant for acquired CPT resistance. Parallel to reduced CPT sensitivity, short hairpin RNA-mediated knockdown of either ISG15 or UbcH8 in ZR-75-1 cells resulted in increased proteasomal degradation of CPT-induced TOP1-DNA covalent complexes. Taken together, these results suggest that ISG15, which interferes with proteasome-mediated repair of TOP1-DNA covalent complexes, is a potential tumor biomarker for CPT sensitivity.

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Published In

Mol Cancer Ther

DOI

ISSN

1535-7163

Publication Date

June 2008

Volume

7

Issue

6

Start / End Page

1430 / 1439

Location

United States

Related Subject Headings

  • Ubiquitins
  • Ubiquitin-Conjugating Enzymes
  • RNA, Small Interfering
  • Oncology & Carcinogenesis
  • Humans
  • Drug Resistance, Neoplasm
  • Down-Regulation
  • DNA Topoisomerases, Type I
  • Cytokines
  • Cell Line, Tumor
 

Citation

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MLA
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Desai, S. D., Wood, L. M., Tsai, Y.-C., Hsieh, T.-S., Marks, J. R., Scott, G. L., … Liu, L. F. (2008). ISG15 as a novel tumor biomarker for drug sensitivity. Mol Cancer Ther, 7(6), 1430–1439. https://doi.org/10.1158/1535-7163.MCT-07-2345
Desai, Shyamal D., Laurence M. Wood, Yu-Chen Tsai, Tao-Shih Hsieh, Jeffrey R. Marks, Georgia L. Scott, Beppino C. Giovanella, and Leroy F. Liu. “ISG15 as a novel tumor biomarker for drug sensitivity.Mol Cancer Ther 7, no. 6 (June 2008): 1430–39. https://doi.org/10.1158/1535-7163.MCT-07-2345.
Desai SD, Wood LM, Tsai Y-C, Hsieh T-S, Marks JR, Scott GL, et al. ISG15 as a novel tumor biomarker for drug sensitivity. Mol Cancer Ther. 2008 Jun;7(6):1430–9.
Desai, Shyamal D., et al. “ISG15 as a novel tumor biomarker for drug sensitivity.Mol Cancer Ther, vol. 7, no. 6, June 2008, pp. 1430–39. Pubmed, doi:10.1158/1535-7163.MCT-07-2345.
Desai SD, Wood LM, Tsai Y-C, Hsieh T-S, Marks JR, Scott GL, Giovanella BC, Liu LF. ISG15 as a novel tumor biomarker for drug sensitivity. Mol Cancer Ther. 2008 Jun;7(6):1430–1439.

Published In

Mol Cancer Ther

DOI

ISSN

1535-7163

Publication Date

June 2008

Volume

7

Issue

6

Start / End Page

1430 / 1439

Location

United States

Related Subject Headings

  • Ubiquitins
  • Ubiquitin-Conjugating Enzymes
  • RNA, Small Interfering
  • Oncology & Carcinogenesis
  • Humans
  • Drug Resistance, Neoplasm
  • Down-Regulation
  • DNA Topoisomerases, Type I
  • Cytokines
  • Cell Line, Tumor