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ISG15 as a novel tumor biomarker for drug sensitivity
Shyamal D Desai1, Laurence M Wood, Yu-Chen Tsai
1Department of Pharmacology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA. sdesai@lsuhsc.edu
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 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.
Insights
Interferon-stimulated gene 15 (ISG15) influences cancer cell sensitivity to camptothecins (CPT) by affecting DNA repair. ISG15 may serve as a biomarker for predicting CPT treatment response.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Tumor cell sensitivity to camptothecins (CPT), such as irinotecan and topotecan, varies significantly, yet the underlying mechanisms remain largely unknown.
- Interferon-stimulated gene 15 (ISG15), a ubiquitin-like protein elevated in many cancers, is known to antagonize the ubiquitin/proteasome pathway.
Purpose of the Study:
- To investigate the role of ISG15 in determining camptothecin (CPT) sensitivity and resistance in tumor cells.
- To explore the potential of ISG15 as a predictive biomarker for CPT treatment response.
Main Methods:
- Utilized short hairpin RNA (shRNA) to knockdown ISG15 and UbcH8 (an E2 enzyme for ISG15) in ZR-75-1 breast cancer cells.
- Analyzed the impact of ISG15 and UbcH8 knockdown on CPT sensitivity and the proteasomal degradation of topoisomerase I (TOP1)-DNA covalent complexes.
Main Results:
- Knockdown of ISG15 or UbcH8 decreased CPT sensitivity in ZR-75-1 cells, suggesting ISG15 overexpression may confer intrinsic resistance.
- ISG15 levels were significantly reduced in CPT-resistant tumor cell lines, indicating altered ISG15 regulation contributes to acquired resistance.
- ISG15 knockdown led to increased proteasomal degradation of CPT-induced TOP1-DNA complexes, correlating with reduced CPT sensitivity.
Conclusions:
- ISG15 plays a crucial role in regulating CPT sensitivity/resistance, potentially by modulating the proteasome-mediated repair of TOP1-DNA covalent complexes.
- ISG15 emerges as a potential tumor biomarker for predicting patient response to CPT-based therapies.
