MCT4 as a potential therapeutic target for metastatic gastric cancer with peritoneal carcinomatosis
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Ji Yun Lee1,*, InKyoung Lee2,*, Won Jin Chang3, Su Min Ahn4,5, Sung Hee Lim1, Hae Su Kim1, Kwai Han Yoo1, Ki Sun Jung1, Haa-Na Song1, Jin Hyun Cho1, Sun Young Kim1, Kyoung-Mee Kim4,5, Soojin Lee1, Seung Tae Kim1, Se Hoon Park1, Jeeyun Lee1, Joon Oh Park1, Young Suk Park1, Ho Yeong Lim1, Won Ki Kang1
1Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
2Biological Research Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
3Division of Hematology-Oncology, Department of Medicine, Korea University College of Medicine, Seoul, Korea
4Innovative Cancer Medicine Institute, Samsung Cancer Center, Samsung Medical Center, Seoul, Korea
5Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
*These authors have contributed equally to this work
Won Ki Kang, e-mail: [email protected]
Keywords: gastric cancer, monocarboxylate transporter, glycolysis, prognosis
Received: October 06, 2015 Accepted: May 05, 2016 Published: May 20, 2016
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.
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