| RRC ID |
52340
|
| 著者 |
Machihara K, Tanaka H, Hayashi Y, Murakami I, Namba T.
|
| タイトル |
Questiomycin A stimulates sorafenib-induced cell death via suppression of glucose-regulated protein 78.
|
| ジャーナル |
Biochem Biophys Res Commun
|
| Abstract |
Hepatocellular carcinoma (HCC) is one of the most difficult cancers to treat owing to the lack of effective chemotherapeutic methods. Sorafenib, the first-line and only available treatment for HCC, extends patient overall survival by several months, with a response rate below 10%. Thus, the identification of an agent that enhances the anticancer effect of sorafenib is critical for the development of therapeutic options for HCC. Endoplasmic reticulum (ER) stress response is one of the methods of sorafenib-induced cell death. Here we report that questiomycin A suppresses expression of GRP78, a cell-protective ER chaperone protein. Analysis of the molecular mechanisms of questiomycin A revealed that this compound stimulated GRP78 protein degradation in an ER stress response-independent manner. Cotreatment with sorafenib and questiomycin A suppressed GRP78 protein expression, which is essential for the stimulation of sorafenib-induced cell death. Moreover, our in vivo study demonstrated that the coadministration of sorafenib and questiomycin A suppressed tumor formation in HCC-induced xenograft models. These results suggest that cotreatment with sorafenib and questiomycin A is a novel therapeutic strategy for HCC by enhancing sorafenib-dependent ER stress-induced cell death, and downregulation of GRP78 is a new target for the stimulation of the therapeutic effects of sorafenib in HCC.
|
| 巻・号 |
492(1)
|
| ページ |
33-40
|
| 公開日 |
2017-10-7
|
| DOI |
10.1016/j.bbrc.2017.08.042
|
| PII |
S0006-291X(17)31594-2
|
| PMID |
28811106
|
| MeSH |
Animals
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Death / drug effects*
Cell Line
Cell Proliferation / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Endoplasmic Reticulum Chaperone BiP
Heat-Shock Proteins / antagonists & inhibitors*
Heat-Shock Proteins / genetics
Heat-Shock Proteins / metabolism
Humans
Liver Neoplasms, Experimental / drug therapy
Liver Neoplasms, Experimental / metabolism
Liver Neoplasms, Experimental / pathology
Male
Mice
Mice, Inbred BALB C
Mice, Nude
Niacinamide / analogs & derivatives*
Niacinamide / chemistry
Niacinamide / pharmacology
Oxazines / chemistry
Oxazines / pharmacology*
Phenylurea Compounds / chemistry
Phenylurea Compounds / pharmacology*
Sorafenib
Structure-Activity Relationship
|
| IF |
2.985
|
| 引用数 |
4
|
| リソース情報 |
| ヒト・動物細胞 |
Hep G2(RCB1886)
PK-1(RCB1972)
KLM-1(RCB2138) |
