Sawako Miyoshi1, Hitoshi Tsugawa2, Juntaro Matsuzaki1, Kenro Hirata1, Hideki Mori1, Hideyuki Saya3, Takanori Kanai1, Hidekazu Suzuki4. 1. Division of Gastroenterology and Hepatology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan. 2. Department of Biochemistry, Keio University School of Medicine, Tokyo, Japan. 3. Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan. 4. Fellowship Training Center and Medical Education Center, Keio University School of Medicine, Tokyo, Japan hsuzuki.a6@keio.jp.
Abstract
BACKGROUND/AIM: Cancer stem cells (CSCs) play a critical role in resistance to chemotherapy. CD44 is a cell surface marker of CSCs. CD44 variant 9 (CD44v9) interacts with a cystine-glutamate antiporter (xCT) and is an unfavorable predictive factor in gastric cancer. We investigated the impact of CD44v9 expression on 5-fluorouracil (5-FU) resistance and the efficacy of the xCT inhibitor, sulfasalazine (SASP), in improving drug resistance. MATERIALS AND METHODS: The human gastric cancer cell line MKN28 was transfected with pRc/CMV plasmids encoding human CD44 or CD44v9, which were used for in vitro and in vivo experiments. RESULTS: CD44v9 expression results in 5-FU resistance by increasing intracellular glutathione and suppressing the drug-induced production of reactive oxygen species (ROS). SASP improved the drug sensitivity of CD44v9-expressing cells. CONCLUSION: Inhibition of xCT improved the clinical efficacy of chemotherapy against gastric cancer. CD44v9 expression can be a novel biomarker to predict resistance against 5-FU in gastric cancer. Copyright
BACKGROUND/AIM: Cancer stem cells (CSCs) play a critical role in resistance to chemotherapy. CD44 is a cell surface marker of CSCs. CD44 variant 9 (CD44v9) interacts with a cystine-glutamate antiporter (xCT) and is an unfavorable predictive factor in gastric cancer. We investigated the impact of CD44v9 expression on 5-fluorouracil (5-FU) resistance and the efficacy of the xCT inhibitor, sulfasalazine (SASP), in improving drug resistance. MATERIALS AND METHODS: The humangastric cancer cell line MKN28 was transfected with pRc/CMV plasmids encoding humanCD44 or CD44v9, which were used for in vitro and in vivo experiments. RESULTS: CD44v9 expression results in 5-FU resistance by increasing intracellular glutathione and suppressing the drug-induced production of reactive oxygen species (ROS). SASP improved the drug sensitivity of CD44v9-expressing cells. CONCLUSION: Inhibition of xCT improved the clinical efficacy of chemotherapy against gastric cancer. CD44v9 expression can be a novel biomarker to predict resistance against 5-FU in gastric cancer. Copyright