Metformin Regulates the Expression of CD133 Through the AMPK-CEBPβ Pathway in Hepatocellular Carcinoma Cell Lines
| Autor: | Naoya Sakamoto, Koji Nakagawa, Goki Suda, Ayaka Asano, Masanobu Kobayashi, Mitsuteru Natsuizaka, Shunsuke Ohnishi, Hiroshi Takeda, Osamu Maehara |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Cancer Research Apoptosis Mice 0302 clinical medicine AMP-Activated Protein Kinase Kinases Gene expression AC133 Antigen LAP Liver-enriched activator protein Regulation of gene expression DMEM Dulbecco's modified Eagle's medium FACS Fluorescence activated cell sorting Chemistry Liver Neoplasms Hep G2 Cells lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Metformin Gene Expression Regulation Neoplastic 030220 oncology & carcinogenesis H&E Hematoxylin and eosin embryonic structures Fluorouracil CSC Cancer stem-like cells Signal Transduction medicine.drug Original article Carcinoma Hepatocellular lcsh:RC254-282 03 medical and health sciences Downregulation and upregulation Cancer stem cell medicine Animals Humans LIP Liver-enriched inhibitory protein CEBPβ CCAAT/enhancer-binding protein beta Protein kinase A PI3K/AKT/mTOR pathway Cell Proliferation CCAAT-Enhancer-Binding Protein-beta AMPK SDS Sodium dodecyl sulfate Xenograft Model Antitumor Assays ACC Acetyl-CoA-carboxylase TBS Tris-buffered saline AMPK AMP-activated protein kinase 030104 developmental biology Drug Resistance Neoplasm Cancer research Protein Kinases |
| Zdroj: | Neoplasia (New York, N.Y.) Neoplasia: An International Journal for Oncology Research, Vol 21, Iss 6, Pp 545-556 (2019) |
| ISSN: | 1476-5586 |
| DOI: | 10.1016/j.neo.2019.03.007 |
| Popis: | CD133 is a cellular surface protein, which has been reported to be a cancer stem cell marker, and thus is considered a potential target for cancer treatment. Metformin, one of the biguanides used for the treatment of diabetes, is also known to reduce the risk of cancer development and cancer stem-like cells (CSCs), including the expression of CD133. However, the mechanism underlying the reduction of the expression of CD133 by metformin is not yet understood. This study shows that metformin suppressed CD133 expression mainly by affecting the CD133 P1 promoter via adenosine monophosphate (AMP)-activated protein kinase (AMPK) signaling but not the mammalian target of rapamycin (mTOR). AMPK inhibition rescued the reduction of CD133 by metformin. Further experiments demonstrated that CCAAT/enhancer-binding protein beta (CEBPβ) was upregulated by metformin and that two isoforms of CEBPβ reciprocally regulated the expression of CD133. Specifically, the liver-enriched activator protein (LAP) isoform increased the expression of CD133 by directly binding to the P1 promoter region, whereas the liver-enriched inhibitory protein (LIP) isoform suppressed the expression of CD133. Consistent with these findings, a three dimensional (3D) culture assay and drug sensitivity assay demonstrated that LAP-overexpressing cells formed large spheroids and were more resistant to 5-fluorouracil (5-FU) treatment, whereas LIP-overexpressing cells were more sensitive to 5-FU and showed combined effects with metformin. Our results indicated that metformin-AMPK-CEBPβ signaling plays a crucial role in regulating the gene expression of CD133. Additionally, regulating the ratio of LAP/LIP may be a novel strategy for targeting CSCs for the treatment of cancer. |
| Databáze: | OpenAIRE |
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