MCT4 as a potential therapeutic target for metastatic gastric cancer with peritoneal carcinomatosis

Abstract

// Ji Yun Lee 1, * , InKyoung Lee 2, * , Won Jin Chang 3 , Su Min Ahn 4, 5 , Sung Hee Lim 1 , Hae Su Kim 1 , Kwai Han Yoo 1 , Ki Sun Jung 1 , Haa-Na Song 1 , Jin Hyun Cho 1 , Sun Young Kim 1 , Kyoung-Mee Kim 4, 5 , Soojin Lee 1 , Seung Tae Kim 1 , Se Hoon Park 1 , Jeeyun Lee 1 , Joon Oh Park 1 , Young Suk Park 1 , Ho Yeong Lim 1 , Won Ki Kang 1 1 Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 2 Biological Research Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 3 Division of Hematology-Oncology, Department of Medicine, Korea University College of Medicine, Seoul, Korea 4 Innovative Cancer Medicine Institute, Samsung Cancer Center, Samsung Medical Center, Seoul, Korea 5 Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea * These authors have contributed equally to this work Correspondence to: Won Ki Kang, e-mail: wkkang@skku.edu Keywords: gastric cancer, monocarboxylate transporter, glycolysis, prognosis Received: October 06, 2015      Accepted: May 05, 2016      Published: May 20, 2016 ABSTRACT Monocarboxylate transporters (MCTs) play a major role in up-regulation of glycolysis and adaptation to acidosis. However, the role of MCTs in gastric cancer (GC) is not fully understood. We investigated the potential utilization of a new cancer therapy for GC. We characterized the expression patterns of the MCT isoforms 1, 2, and 4 and investigated the role of MCT in GC through in vitro and in vivo tests using siRNA targeting MCTs. In GC cell lines, MCT1, 2, and 4 were up-regulated with different expression levels; MCT1 and MCT4 were more widely expressed in GC cell lines compared with MCT2. Inhibition of MCTs by siRNA or AR-C155858 reduced cell viability and lactate uptake in GC cell lines. The effect of inhibition of MCTs on tumor growth was also confirmed in xenograft models. Furthermore, MCT inhibition in GC cells increased the sensitivity of cells to radiotherapy or chemotherapy. Compared with normal gastric tissue, no significant alterations of expression levels in tumors were identified for MCT1 and MCT2, whereas a significant increase in MCT4 expression was observed. Most importantly, MCT4 was highly overexpressed in malignant cells of acsites and its silencing resulted in reduced tumor cell proliferation and lactate uptake in malignant ascites. Our study suggests that MCT4 is a clinically relevant target in GC with peritoneal carcinomatosis.