Abstract B54: Type II interleukin 1 receptor-modulated SET/PP2A/p-ERK signaling is associated with regorafenib resistance in human colorectal cancer cells
| Autor: | Chun-Ho Chu, Chung Wai Shiau, Te-Chang Lee, Shung Haur Yang, Jeng-Kai Jiang, Ai-Chung Mar |
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| Rok vydání: | 2015 |
| Předmět: | |
| Zdroj: | Molecular Cancer Therapeutics. 14:B54-B54 |
| ISSN: | 1538-8514 1535-7163 |
| DOI: | 10.1158/1535-7163.targ-15-b54 |
| Popis: | Regorafenib, a newly approved multi-kinase inhibitor by US FDA, has recently demonstrated overall survival benefits in late-stage colorectal cancer (CRC) patients. We have observed that the expression type II interleukin 1 receptor (IL1R2), an IL-1 decoy receptor, were closely associated with regorafenib resistance in human CRC cells. In addition, IL1R2 expression was associated with poor prognosis of patients with CRC cancer. In this study, we conducted experiments to elucidate the roles of IL1R2 in regorafenib resistance. We first demonstrated that silencing of IL1R2 in HT29 cells by shRNA overcame their resistance to regorafenib, whereas ectopic expression of IL1R2 in HCT116 cells increased their resistance to regorafenib in either in vitro or in vivo systems. We further established regorafenib-resistant DLD-1 cells (DLD-1-R) by long-term culturing DLD-1 cells in the presence of regorafenib. Our results demonstrated increased expression of IL1R2 in DLD-1-R cells compared to parental DLD-1 cells. We observed that IL1R2 expression is associated with p-ERK level, which is crucial for survival of cancer cells. Pretreatment of HT29, IL1R2-overexpressing HCT116, and DLD-1-R cells with MEK/ERK inhibitor U0126 significantly reversed their resistance to regorafenib. Mechanistically, we revealed that SET/PP2A signaling plays crucial role on increasing p-ERK levels in IL1R2-overexpressing cells. Taken together, our present study suggested that enhanced IL1R2 mediates through SET/PP2A/p-ERK signaling to induce regorafenib resistance and, therefore, IL1R2 associated regorafenib resistance is overcome by combination treatment of CRC patients with regorafenib and MEK/ERK inhibitor. Citation Format: Ai-Chung Mar, Chun-Ho Chu, Shung-Haur Yang, Jeng-Kai Jiang, Chung-Wai Shiau, Te-Chang Lee. Type II interleukin 1 receptor-modulated SET/PP2A/p-ERK signaling is associated with regorafenib resistance in human colorectal cancer cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B54. |
| Databáze: | OpenAIRE |
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