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.

Biological evaluation of [18F]AlF-NOTA-NSC-GLU as a PET tracer for hepatocellular carcinoma

“…xCT, the member of system X C transporter, is actively expressed in HCC patients [45]. Cyss, as a substrate of X C system, did not markedly inhibit the uptake of this agent.…”

“…The mice were injected intravenously (IV) with 20-40 μCi of [ 18 F]AlF-NOTA-NSC-GLU in 0.2 mL of saline. At 15,30,45,60, and 90 min after injection, the distribution of the tracer in selected organs were evaluated. Organs of interest (blood, brain, heart, lung, liver, spleen, kidneys, pancreas, stomach, intestine, muscle, and bone) were weighed and 18 F radioactivity was counted with a γ-counter.…”

The Prognostic Roles and Clinical Features of CD44v9 in Human Solid Cancers—A Meta-Analysis

“…Within cancer cells, CD44v9 interacts with the subunit cystine/glutamate antiporter (xCT) to promote intracellular synthesis of the antioxidant glutathione (GSH) [31]. This response can enhance the defense against reactive oxygen species (ROS) and promote tumor growth [32,33].…”

“…This response can enhance the defense against reactive oxygen species (ROS) and promote tumor growth [32,33]. Some anti-tumor drugs targeting this mechanism may be more effective in controlling tumor progression [29,31,34].…”

Inhibiting xCT/SLC7A11 induces ferroptosis of myofibroblastic hepatic stellate cells and protects against liver fibrosis

“…6 RSL3 acts downstream of xCT to induce ferroptosis by directly inhibiting GPX4. 6 Although xCT was reported to increase during toxic liver injury and in hepatocellular carcinoma (HCC), [7][8][9] its role in MF-HSC has never been investigated and thus, the impact of xCT activity on liver fibrosis progression remains unclear.…”