| RRC ID |
55977
|
| 著者 |
Wada F, Koga H, Akiba J, Niizeki T, Iwamoto H, Ikezono Y, Nakamura T, Abe M, Masuda A, Sakaue T, Tanaka T, Kakuma T, Yano H, Torimura T.
|
| タイトル |
High expression of CD44v9 and xCT in chemoresistant hepatocellular carcinoma: Potential targets by sulfasalazine.
|
| ジャーナル |
Cancer Sci
|
| Abstract |
CD44v9 is expressed in cancer stem cells (CSC) and stabilizes the glutamate-cystine transporter xCT on the cytoplasmic membrane, thereby decreasing intracellular levels of reactive oxygen species (ROS). This mechanism confers ROS resistance to CSC and CD44v9-expressing cancer cells. The aims of the present study were to assess: (i) expression status of CD44v9 and xCT in hepatocellular carcinoma (HCC) tissues, including those derived from patients treated with hepatic arterial infusion chemoembolization (HAIC) therapy with cisplatin (CDDP); and (ii) whether combination of CDDP with sulfasalazine (SASP), an inhibitor of xCT, was more effective on tumor cells than CDDP alone by inducing ROS-mediated apoptosis. Twenty non-pretreated HCC tissues and 7 HCC tissues administered HAIC therapy with CDDP before surgical resection were subjected to immunohistochemistry analysis of CD44v9 and xCT expression. Human HCC cell lines HAK-1A and HAK-1B were used in this study; the latter was also used for xenograft experiments in nude mice to assess in vivo efficacy of combination treatment. CD44v9 positivity was significantly higher in HAIC-treated tissues (5/7) than in non-pretreated tissues (2/30), suggesting the involvement of CD44v9 in the resistance to HAIC. xCT was significantly expressed in poorly differentiated HCC tissues. Combination treatment effectively killed the CD44v9-harboring HAK-1B cells through ROS-mediated apoptosis and significantly decreased xenografted tumor growth. In conclusion, the xCT inhibitor SASP augmented ROS-mediated apoptosis in CDDP-treated HCC cells, in which the CD44v9-xCT system functioned. As CD44v9 is typically expressed in HAIC-resistant HCC cells, combination treatment with SASP with CDDP may overcome such drug resistance.
|
| 巻・号 |
109(9)
|
| ページ |
2801-2810
|
| 公開日 |
2018-9-1
|
| DOI |
10.1111/cas.13728
|
| PMID |
29981246
|
| PMC |
PMC6125439
|
| MeSH |
Aged
Aged, 80 and over
Amino Acid Transport System y+ / analysis
Amino Acid Transport System y+ / physiology*
Animals
Apoptosis / drug effects
Carcinoma, Hepatocellular / chemistry
Carcinoma, Hepatocellular / drug therapy*
Cisplatin / pharmacology
Drug Resistance, Neoplasm
Female
Hep G2 Cells
Humans
Hyaluronan Receptors / analysis
Hyaluronan Receptors / physiology*
Liver Neoplasms / chemistry
Liver Neoplasms / drug therapy*
Male
Mice
Mice, Inbred BALB C
Middle Aged
Reactive Oxygen Species / metabolism
Sulfasalazine / pharmacology*
|
| IF |
4.751
|
| 引用数 |
7
|
| リソース情報 |
| ヒト・動物細胞 |
HCT116(RCB2979) |
