ISG15 as a novel tumor biomarker for drug sensitivity

Shyamal D. Desai, Laurence M. Wood, Yu Chen Tsai, Tao Shih Hsieh, Jeffrey R. Marks, Georgia L. Scott, Beppino C. Giovanella, Leroy-Fong Liu

Research output: Contribution to journalArticle

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Abstract

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 RNAmediated 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.

Original languageEnglish
Pages (from-to)1430-1439
Number of pages10
JournalMolecular Cancer Therapeutics
Volume7
Issue number6
DOIs
Publication statusPublished - 2008
Externally publishedYes

Fingerprint

Tumor Biomarkers
Pharmaceutical Preparations
Genes
Proteasome Endopeptidase Complex
irinotecan
Neoplasms
Ubiquitins
Topotecan
Camptothecin
Type I DNA Topoisomerase
Intrinsic Factor
Ubiquitin
Tumor Cell Line
DNA Repair
Small Interfering RNA
Breast Neoplasms
DNA

ASJC Scopus subject areas

  • Oncology
  • Cancer Research
  • Drug Discovery
  • Pharmacology

Cite this

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. Molecular Cancer Therapeutics, 7(6), 1430-1439. https://doi.org/10.1158/1535-7163.MCT-07-2345

ISG15 as a novel tumor biomarker for drug sensitivity. / Desai, Shyamal D.; Wood, Laurence M.; Tsai, Yu Chen; Hsieh, Tao Shih; Marks, Jeffrey R.; Scott, Georgia L.; Giovanella, Beppino C.; Liu, Leroy-Fong.

In: Molecular Cancer Therapeutics, Vol. 7, No. 6, 2008, p. 1430-1439.

Research output: Contribution to journalArticle

Desai, SD, Wood, LM, Tsai, YC, Hsieh, TS, Marks, JR, Scott, GL, Giovanella, BC & Liu, L-F 2008, 'ISG15 as a novel tumor biomarker for drug sensitivity', Molecular Cancer Therapeutics, vol. 7, no. 6, pp. 1430-1439. https://doi.org/10.1158/1535-7163.MCT-07-2345
Desai SD, Wood LM, Tsai YC, Hsieh TS, Marks JR, Scott GL et al. ISG15 as a novel tumor biomarker for drug sensitivity. Molecular Cancer Therapeutics. 2008;7(6):1430-1439. https://doi.org/10.1158/1535-7163.MCT-07-2345
Desai, Shyamal D. ; Wood, Laurence M. ; Tsai, Yu Chen ; Hsieh, Tao Shih ; Marks, Jeffrey R. ; Scott, Georgia L. ; Giovanella, Beppino C. ; Liu, Leroy-Fong. / ISG15 as a novel tumor biomarker for drug sensitivity. In: Molecular Cancer Therapeutics. 2008 ; Vol. 7, No. 6. pp. 1430-1439.
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