Glibenclamide Targets Sulfonylurea Receptor 1 to Inhibit p70S6K Activity and Upregulate KLF4 Expression to Suppress Non-Small Cell Lung Carcinoma
| Autor: | Wenbin Huang, Min Li, Geng Sun, Xuerong Wang, Zuhao Zhang, Kexin Xu, Hongling Chen, Lin Xu, Xixi Qian, Ping Li |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
endocrine system Cancer Research Lung Neoplasms Tumor suppressor gene Cell Survival Cell Kruppel-Like Transcription Factors Sulfonylurea Receptors Glibenclamide Kruppel-Like Factor 4 Mice 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Carcinoma Non-Small-Cell Lung Cell Line Tumor Glyburide medicine Animals Humans Gene silencing Phosphorylation Cell Proliferation A549 cell Chemistry Cell growth Ribosomal Protein S6 Kinases 70-kDa DNA Methylation Survival Analysis Xenograft Model Antitumor Assays Up-Regulation 030104 developmental biology medicine.anatomical_structure Oncology A549 Cells 030220 oncology & carcinogenesis Cancer research Sulfonylurea receptor Female Signal Transduction medicine.drug |
| Zdroj: | Molecular Cancer Therapeutics. 18:2085-2096 |
| ISSN: | 1538-8514 1535-7163 |
| DOI: | 10.1158/1535-7163.mct-18-1181 |
| Popis: | Sulfonylurea receptor 1 (SUR1) is the regulatory subunit of ATP-sensitive potassium channels (KATP channels) and the receptor of antidiabetic drugs, such as glibenclamide, which induce insulin secretion in pancreatic β cells. However, the expression and role of SUR1 in cancer are unknown. In this study, we found that SUR1 expression was elevated in human non–small cell lung carcinoma (NSCLC) tissues and cell lines. SUR1 silencing suppressed the growth of NSCLC cells, while SUR1 overexpression promoted cell growth. Targeting SUR1 with glibenclamide suppressed cell growth, cell-cycle progression, epithelial–mesenchymal transition (EMT), and cell migration. Moreover, SUR1 directly interacted with p70S6K and upregulated p70S6K phosphorylation and activity. In addition, glibenclamide inhibited p70S6K, and overexpression of p70S6K partially reversed the growth-inhibiting effect of glibenclamide. Furthermore, glibenclamide upregulated the expression of the tumor suppressor Krüppel-like factor 4 (KLF4), and silencing KLF4 partially reversed the inhibitory effect of glibenclamide on cell growth, EMT, and migration. We found that SUR1 targeted p70S6K to downregulate KLF4 expression by enhancing DNA-methyltransferase 1–mediated methylation of the KLF4 promoter. Finally, in xenograft mouse models, SUR1 expression silencing or glibenclamide treatment inhibited the growth of A549 tumors, downregulated p70S6K activity, and upregulated KLF4 expression. These findings suggested that SUR1 expression was elevated in some NSCLC tissues and functioned as a tumor enhancer. Targeting SUR1 with glibenclamide inhibited NSCLC through downregulation of p70S6K activity and subsequent upregulation of the expression of the tumor suppressor gene KLF4. SUR1 can be developed as a new target for cancer therapy and glibenclamide has potential anticancer effects. |
| Databáze: | OpenAIRE |
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