Oncotarget

Research Papers:

Impact of the glutathione synthesis pathway on sulfasalazine-treated endometrial cancer

Kanako Sendo, Manabu Seino _, Tsuyoshi Ohta and Satoru Nagase

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Abstract

Kanako Sendo1, Manabu Seino1, Tsuyoshi Ohta1 and Satoru Nagase1

1 Department of Obstetrics and Gynecology, Yamagata University Faculty of Medicine, Yamagata, Japan

Correspondence to:

Manabu Seino, email: m-seino@med.id.yamagata-u.ac.jp

Keywords: endometrial cancer; glutathione; sulfasalazine; xCT; cystathionine gamma-lyase

Received: September 28, 2021     Accepted: January 10, 2022     Published: January 26, 2022

Copyright: © 2022 Sendo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

ABSTRACT

Glutathione is an antioxidant that has an important role in chemotherapeutic drug resistance in cancer. Cysteine is synthesized from cystine and is transported into the cell via the xCT antiporter. Another pathway for synthesizing cysteine involves intracellular methionine. We determined whether targeting the xCT represents a promising strategy for the treatment of endometrial cancer and identified factors that predict efficacy of this treatment strategy. In uterine serous carcinoma (USC) cell lines, the combination of cisplatin and the xCT inhibitor, sulfasalazine, significantly inhibited cell growth compared with single-agent cisplatin or sulfasalazine. Sulfasalazine treatment significantly decreased intracellular glutathione levels and induced apoptosis when combined with cisplatin in USC cell lines. On the one hand, the effectiveness of combined cisplatin and sulfasalazine was not evident in endometrioid carcinoma. USC cell lines exhibited increased expression of xCT and decreased expression of cystathionine gamma lyase (CGL), which is an enzyme involved in the synthesis of cysteine from methionine. On the other hand, endometrioid carcinoma cell lines exhibited increased CGL expression or decreased xCT expression. These findings suggest that using a glutathione synthesis pathway-based approach for selecting subjects for sulfasalazine treatment may be an effective strategy for circumventing glutathione-related chemotherapeutic drug resistance in endometrial carcinoma.


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