siRNA-mediated inactivation of HER3 improves the antitumour activity and sensitivity of gefitinib in gastric cancer cells
| Autor: | Zhen-Zhen Li, Lei Liu, Li Ying Wang, Ying-nan Yang, Wenjie Zhang, Jianhua Zhou, Jun-Wei Qin, Xiaoli Wei, Xiao-Xue Du, Tao Liu, Yanjing Li, Peng Huang, Qingxin Zhou, Heng-heng Yuan, Ting-Ting Zhang, Yu Han |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway gefitinib Receptor tyrosine kinase 03 medical and health sciences 0302 clinical medicine Gefitinib HER3 Medicine ERBB3 Kinase activity skin and connective tissue diseases neoplasms Protein kinase B EGFR inhibitors PI3K/AKT Traditional medicine biology business.industry gastric cancer body regions 030104 developmental biology Oncology siRNA 030220 oncology & carcinogenesis Cancer research biology.protein business Tyrosine kinase Research Paper medicine.drug |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| DOI: | 10.18632/oncotarget.17526 |
| Popis: | The human EGFR family consists of four type-1 transmembrane tyrosine kinase receptors: HER1 (EGFR, ErbB1), HER2 (Neu, ErbB2), HER3 (ErbB3), and HER4 (ErbB4). HER3 can dimerize with EGFR, HER2 and even c-Met and likely plays a central role in the response to EGFR-targeted therapy. Because HER3 lacks significant kinase activity and cannot be inhibited by tyrosine kinase inhibitors, neutralizing antibodies and alternative inhibitors of HER3 have been sought as cancer therapeutics. Here, we describe the stable suppression of HER3 mRNA and protein using siRNA. The inhibition of HER3 expression decreased cell proliferation, suppressed cell cycle progression, induced apoptosis and inhibited cell motility, migration, invasiveness, and soft agar growth. In addition, we found that gefitinib treatment increased the HER3 and HER2 mRNA levels. The administration of various concentrations of gefitinib to HER3-knockdown cells enhanced antitumour activity and sensitivity due to the downregulation of protein phosphorylation via PI3K/AKT and ERK signalling. Our results support the use of combined treatments targeting multiple EGFR receptors, particularly the use of HER3 inhibitors combined with EGFR inhibitors, such as gefitinib. |
| Databáze: | OpenAIRE |
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