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High expression of CD44v9 and xCT in chemoresistant hepatocellular carcinoma: Potential targets by sulfasalazine.

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.

SUBMITTER: Wada F

PROVIDER: S-EPMC6125439 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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High expression of CD44v9 and xCT in chemoresistant hepatocellular carcinoma: Potential targets by sulfasalazine.

Wada Fumitaka F Koga Hironori H Akiba Jun J Niizeki Takashi T Iwamoto Hideki H Ikezono Yu Y Nakamura Toru T Abe Mitsuhiko M Masuda Atsutaka A Sakaue Takahiko T Tanaka Toshimitsu T Kakuma Tatsuyuki T Yano Hirohisa H Torimura Takuji T

Cancer science 20180816 9

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 chemoembol ...[more]

PMID: 29981246

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High expression of CD44v9 and xCT in chemoresistant hepatocellular carcinoma: Potential targets by sulfasalazine.

Publications

High expression of CD44v9 and xCT in chemoresistant hepatocellular carcinoma: Potential targets by sulfasalazine.

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