2. Academic Validation
  3. Chemotherapy-induced cell cycle arrest is associated with increased claudin-18 isoform 2 expression and enhanced zolbetuximab-mediated cytotoxicity in gastric cancer

Chemotherapy-induced cell cycle arrest is associated with increased claudin-18 isoform 2 expression and enhanced zolbetuximab-mediated cytotoxicity in gastric cancer

  • J Gastroenterol. 2026 May 14. doi: 10.1007/s00535-026-02443-z.
Chiaki Takiguchi 1,  Shotaro Nakajima 2 3,  Hajime Matsuida 1,  Hiroyuki Hanayama 1,  Akira Matsuishi 1,  Katsuharu Saito 1,  Sohei Hayashishita 1,  Dai Mitsui 1,  Ayumi Fujii 1,  Daiki Yamaguchi 1,  Motonobu Saito 1,  Hirokazu Okayama 1,  Kosaku Mimura 1 4,  Hiroshi Nakano 1,  Tomohiro Kikuchi 1,  Zenichiro Saze 1,  Tomoyuki Momma 1,  Rei Sekine 5,  Koji Kono 1 6
Affiliations

Affiliations

  • 1 Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan.
  • 2 Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan. [email protected].
  • 3 Department of Multidisciplinary Treatment of Cancer and Regional Medical Support, Fukushima Medical University, 1 Hikariga-Oka, Fukushima City, Fukushima, 960-1295, Japan. [email protected].
  • 4 Department of Blood Transfusion and Transplantation Immunology, Fukushima Medical University School of Medicine, Fukushima, Japan.
  • 5 Department of Diagnostic Pathology, Fukushima Medical University School of Medicine, Fukushima, Japan.
  • 6 Department of Multidisciplinary Treatment of Cancer and Regional Medical Support, Fukushima Medical University, 1 Hikariga-Oka, Fukushima City, Fukushima, 960-1295, Japan.
PMID: 42133042 DOI: 10.1007/s00535-026-02443-z
Abstract

Background: Claudin-18 isoform 2 (CLDN18.2) is a tight junction protein expressed in gastric mucosa and gastric Cancer (GC) cells. Although chemotherapeutic agents are suggested to increase CLDN18.2 expression in GC cells, their impact on GC tissues and their underlying mechanisms remain unclear.

Methods: We examined the effects of chemotherapy on CLDN18.2 expression in human GC tissues and cell lines, and investigated the role of cell-cycle regulation in this process.

Results: We found that CLDN18.2 expression was upregulated in GC tissues after chemotherapy. In GC cell lines (SNU-601, NUGC4, GSU), chemotherapeutic agents, including 5-fluorouracil, irinotecan, paclitaxel, and cisplatin, increased CLDN18.2 expression at the transcriptional level, although the response patterns varied among cell lines and agents. Since cell-cycle regulation appeared to be involved, we tested cyclin-dependent kinase (CDK) inhibitors and found that CDK1- and CDK4/6-specific inhibitors similarly enhanced CLDN18.2 expression. Importantly, both chemotherapeutic agents and CDK inhibitors significantly increased zolbetuximab-mediated antibody-dependent cellular cytotoxicity in GC cells.

Conclusion: These results suggest that chemotherapeutic agents upregulate CLDN18.2 in GC cells at least in part through cell cycle arrest, and support combining zolbetuximab with chemotherapy and/or CDK inhibitors for GC treatment.

Keywords

Cell cycle; Chemotherapy; Claudin-18 isoform 2; Cyclin-dependent kinase; Gastric cancer.

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