Editorial
Copyright ©2011 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Gastrointest Oncol. Aug 15, 2011; 3(8): 119-122
Published online Aug 15, 2011. doi: 10.4251/wjgo.v3.i8.119
Intracellular chloride regulates the G1/S cell cycle progression in gastric cancer cells
Atsushi Shiozaki, Eigo Otsuji, Yoshinori Marunaka
Atsushi Shiozaki, Eigo Otsuji, Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
Yoshinori Marunaka, Department of Molecular Cell Physiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan; Japan Institute for Food Education and Health, St. Agnes’ University, Kyoto 602-8013, Japan
Author contributions: Shiozaki A carried out the experiments for this review and wrote the manuscript; Otsuji E supervised the research; Marunaka Y designed the experiments and supervised the research.
Correspondence to: Dr. Atsushi Shiozaki, Assistant Professor, Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto 602-8566, Japan. shiozaki@koto.kpu-m.ac.jp
Telephone: +81-75-2515527 Fax: +81-75-2515522
Received: March 31, 2011
Revised: July 25, 2011
Accepted: August 1, 2011
Published online: August 15, 2011
Abstract

Recent studies show that ion channels/transporters play important roles in fundamental cellular functions. Several reports indicating the important roles of Cl- channels/transporters on cell proliferation suggest that the intracellular chloride concentration ([Cl-]i) regulated by them would be one of critical messengers. We investigated whether the [Cl-]i controls cell proliferation and cell cycle progression in human gastric cancer cells. Our studies indicated that furosemide, a blocker of Na+/K+/2Cl- cotransporter (NKCC), diminished cell growth by delaying the G1-S phase progression in gastric cancer cells with high expression and activity of NKCC. Furthermore, we found that the culture in the low Cl- medium (replacement of Cl- by NO3-) decreased the [Cl-]i and inhibited cell growth of gastric cancer cells and that this inhibition of cell growth was due to cell cycle arrest at the G0/G1 phase caused by diminution of CDK2 and phosphorylated Rb. The culture of cells in the low Cl- medium significantly increased expressions of p21 mRNA and protein. In addition, the low Cl- medium induced phosphorylation of mitogen activated protein kinases (MAPKs). Treatment with an inhibitor of p38 or JNK significantly suppressed p21 upregulation caused by culture in a low Cl- medium and rescued gastric cancer cells from the low Cl--induced G1 cell cycle arrest. These findings revealed that the [Cl-]i affects the cell proliferation via activation of MAPKs through upregulation of p21 in gastric cancer cells. Our results suggest that the [Cl-]i regulates important cellular functions in gastric cancer cells, leading to the development of novel therapeutic strategies.

Keywords: Intracellular chloride; Cell proliferation; Cell cycle; Gastric cancer; Cl- channel; Cl- transporter