| RRC ID |
57773
|
| 著者 |
Maehara O, Ohnishi S, Asano A, Suda G, Natsuizaka M, Nakagawa K, Kobayashi M, Sakamoto N, Takeda H.
|
| タイトル |
Metformin Regulates the Expression of CD133 Through the AMPK-CEBPβ Pathway in Hepatocellular Carcinoma Cell Lines.
|
| ジャーナル |
Neoplasia
|
| Abstract |
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.
|
| 巻・号 |
21(6)
|
| ページ |
545-556
|
| 公開日 |
2019-6-1
|
| DOI |
10.1016/j.neo.2019.03.007
|
| PII |
S1476-5586(19)30062-4
|
| PMID |
31042624
|
| PMC |
PMC6488768
|
| MeSH |
AC133 Antigen / genetics*
AMP-Activated Protein Kinase Kinases
Animals
Apoptosis / drug effects
CCAAT-Enhancer-Binding Protein-beta / genetics*
Carcinoma, Hepatocellular / drug therapy*
Carcinoma, Hepatocellular / genetics
Carcinoma, Hepatocellular / pathology
Cell Proliferation / drug effects
Drug Resistance, Neoplasm / genetics
Fluorouracil / pharmacology
Gene Expression Regulation, Neoplastic / drug effects
Hep G2 Cells
Humans
Liver Neoplasms / drug therapy*
Liver Neoplasms / genetics
Liver Neoplasms / pathology
Metformin / pharmacology
Mice
Protein Kinases / genetics*
Signal Transduction / drug effects
Xenograft Model Antitumor Assays
|
| IF |
5.696
|
| 引用数 |
3
|
| リソース情報 |
| ヒト・動物細胞 |
Hep G2(RCB1886) |
