| RRC ID |
44702
|
| 著者 |
Hou H, Sun H, Lu P, Ge C, Zhang L, Li H, Zhao F, Tian H, Zhang L, Chen T, Yao M, Li J.
|
| タイトル |
Tunicamycin potentiates cisplatin anticancer efficacy through the DPAGT1/Akt/ABCG2 pathway in mouse Xenograft models of human hepatocellular carcinoma.
|
| ジャーナル |
Mol Cancer Ther
|
| Abstract |
Hepatocellular carcinoma is highly chemoresistant, and ATP-binding cassette subfamily G member 2 (ABCG2) is thought to play a critical role in this drug resistance. The present study aims to develop effective therapeutic strategies to decrease ABCG2 expression level and to surmount drug resistance in hepatocellular carcinoma chemotherapy. First, we verified a positive correlation between the ABCG2 protein level and the drug resistance of hepatocellular carcinoma cell lines. ABCG2 was preferentially expressed in highly chemoresistant hepatocellular carcinoma cancer stem cells (CSC) enriched with CD133. In addition, ABCG2 was N-linked glycosylated in hepatocellular carcinoma cells, and this modification was involved in sustaining its protein stability. The N-linked glycosylation (NLG) inhibitor tunicamycin dramatically reduced ABCG2 expression, altered its subcellular localization, and reversed its drug efflux effect in multiple hepatocellular carcinoma cell lines. Furthermore, tunicamycin reduced the expression levels of several CSC markers and suppressed the tumorigenicity of CD133(+) CSCs. Tunicamycin combined with cisplatin (CDDP) inhibited proliferating cell nuclear antigen (PCNA) expression and increased the cleavage of PARP; this effect was partially rescued by the overexpression of ABCG2 or Akt-myr. The combination therapy more effectively suppressed tumor growth in xenograft mice than did single-agent therapy with either drug. Finally, the CDDP treatment combined with UDP-GlcNAc-dolichol-phosphate N-acetylglucosamine-1 phosphate transferase (DPAGT1) knockdown recapitulated the effect observed when CDDP was used in combination with tunicamycin. In summary, our results suggest that tunicamycin may reverse the drug resistance and improve the efficacy of combination treatments for hepatocellular carcinomas by targeting the DPAGT1/Akt/ABCG2 pathway.
|
| 巻・号 |
12(12)
|
| ページ |
2874-84
|
| 公開日 |
2013-12-1
|
| DOI |
10.1158/1535-7163.MCT-13-0201
|
| PII |
1535-7163.MCT-13-0201
|
| PMID |
24130050
|
| MeSH |
ATP Binding Cassette Transporter, Subfamily G, Member 2
ATP-Binding Cassette Transporters / genetics
ATP-Binding Cassette Transporters / metabolism*
Animals
Antineoplastic Agents / pharmacology*
Carcinoma, Hepatocellular / genetics
Carcinoma, Hepatocellular / metabolism*
Carcinoma, Hepatocellular / pathology
Cell Line, Tumor
Cisplatin / pharmacology*
Disease Models, Animal
Drug Synergism
Humans
Intracellular Space / metabolism
Liver Neoplasms / genetics
Liver Neoplasms / metabolism*
Liver Neoplasms / pathology
Mice
N-Acetylglucosaminyltransferases / metabolism*
Neoplasm Proteins / genetics
Neoplasm Proteins / metabolism*
Neoplastic Stem Cells / drug effects
Neoplastic Stem Cells / metabolism
Protein Transport
Proto-Oncogene Proteins c-akt / metabolism*
Signal Transduction
Tunicamycin / pharmacology*
Xenograft Model Antitumor Assays
|
| IF |
5.615
|
| 引用数 |
32
|
|
WOS 分野
|
ONCOLOGY
|
| リソース情報 |
| ヒト・動物細胞 |
HuH-7 |
