Inhibiting xCT Improves 5-Fluorouracil Resistance of Gastric Cancer Induced by CD44 Variant 9 Expression.

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.

• Authors: Sawako Miyoshi, Hitoshi Tsugawa, Juntaro Matsuzaki, Kenro Hirata, Hideki Mori, Hideyuki Saya, Takanori Kanai, Hidekazu Suzuki
• Journal: Anticancer research (Anticancer Res) Vol. 38 Issue 11 Pg. 6163-6170 (Nov 2018) ISSN: 1791-7530 [Electronic] Greece
• PMID: 30396933 (Publication Type: Journal Article)
• Copyright: Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Chemical References

• Amino Acid Transport System y+
• CD44v9 antigen
• Hyaluronan Receptors
• Reactive Oxygen Species
• SLC7A11 protein, human
• Sulfasalazine
• Glutathione
• Fluorouracil

Topics

• Amino Acid Transport System y+ (antagonists & inhibitors, metabolism)
• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Drug Resistance, Neoplasm
• Drug Synergism
• Female
• Fluorouracil (administration & dosage, pharmacology)
• Glutathione (metabolism)
• Humans
• Hyaluronan Receptors (biosynthesis, genetics)
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Reactive Oxygen Species (metabolism)
• Stomach Neoplasms (drug therapy, genetics, metabolism)
• Sulfasalazine (administration & dosage, pharmacology)
• Transfection
• Xenograft Model Antitumor Assays