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.
Highlights
Gastric cancer (GC) is the fourth most common cancer and the second leading cause of cancer deaths globally [1]
MCT1 was expressed in almost all gastric cancer (GC) cell lines, whereas MCT4 was primarily expressed in cell lines derived from metastasis or ascites
Our results provided the first evidence that MCT4 might be a potential therapeutic target for GC with peritoneal carcinomatosis
Summary
Gastric cancer (GC) is the fourth most common cancer and the second leading cause of cancer deaths globally [1]. In advanced and metastatic gastric cancer, conventional chemotherapy with limited efficacy shows a median overall survival (OS) of less than 1 year [2, 3]. In rapidly growing cancer cells, oncogenes and hypoxia stimulate the glycolytic metabolism, which generates increased amounts of lactic and carbonic acids [6,7,8]. The MCT family comprises 14 members, among which only the first 4 (MCT1, 2, 3, and 4) catalyze the proton-linked transport of metabolically important monocarboxylates, such as lactate, pyruvate, and ketone bodies [10]. MCT3 is uniquely expressed in the retinal pigment epithelium [12], whereas MCT4 is primarily expressed in highly glycolytic cells, where it is used to facilitate lactic acid effuse from the tissue [13]
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