Activation of insulin-like growth factor receptor signaling mediates resistance to histone deacetylase inhibitors
| Autor: | So Jung Kwon, Ho-Young Lee, Hyo Jong Lee, Su Chan Lee, Woo-Young Kim, Hye-Young Min, Kwan Hee Park, Seung Yeob Hyun, Sun Phil Choi, Jin-Soo Kim |
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| Rok vydání: | 2015 |
| Předmět: |
Epigenomics
Cancer Research Lung Neoplasms medicine.drug_class Gene Expression Mice Nude Biology Hydroxamic Acids Receptor IGF Type 1 Mice chemistry.chemical_compound Growth factor receptor Carcinoma Non-Small-Cell Lung Cell Line Tumor medicine Animals Humans Vorinostat Cell Proliferation Depsipeptide Histone deacetylase 5 Histone deacetylase inhibitor Sodium butyrate Xenograft Model Antitumor Assays Histone Deacetylase Inhibitors Trichostatin A Oncology chemistry Drug Resistance Neoplasm Cancer research Female Histone deacetylase medicine.drug |
| Zdroj: | Cancer Letters. 361:197-206 |
| ISSN: | 0304-3835 |
| DOI: | 10.1016/j.canlet.2015.02.038 |
| Popis: | Histone deacetylases (HDACs) are considered promising targets in the treatment of hematologic malignancies and several types of solid tumors, including non-small cell lung cancer (NSCLC). However, the efficacy of HDAC inhibitors in solid tumors is marginal, and the mechanisms underlying resistance to HDAC inhibitors are largely unknown. Here, we demonstrate the involvement of type 1 insulin-like growth factor receptor (IGF-1R) signaling in resistance to HDAC inhibitors in NSCLC. Using MTT and soft-agar colony formation assays, we selected NSCLC cell lines that exhibited intrinsic resistance to vorinostat. Treatment with vorinostat activated IGF-1R signaling in vorinostat-resistant but not vorinostat-sensitive NSCLC cells. Other HDAC inhibitors, including trichostatin A, sodium butyrate, and depsipeptide, also activated IGF-1R signaling in vorinostat-resistant NSCLC cells. Blockade of IGF-1R signaling via IGF-1R monoclonal antibodies (mAbs) or through knockdown of IGF-1R via RNA interference sensitized vorinostat-resistant cells to HDAC inhibition. Finally, IGF-1R mAbs sensitized xenograft tumors of vorinostat-resistant cells to vorinostat treatment in vivo. These findings suggest that IGF-1R activation is generally involved in resistance to HDAC inhibitors and that targeting IGF-1R is an effective strategy for overcoming resistance to HDAC inhibitors in NSCLC. |
| Databáze: | OpenAIRE |
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