MACC1 mediates chemotherapy sensitivity of 5-FU and cisplatin via regulating MCT1 expression in gastric cancer

Chemotherapeutic insensitivity is a main obstacle for effective treatment of gastric Cancer (GC), the underlying mechanism remains to be investigated. Metastasis-associated in colon cancer-1 (MACC1), a transcription factor highly expressed in GC, is found to be related to chemotherapy sensitivity. Monocarboxylate Transporter 1 (MCT1), a plasma membrane protein co-transporting lactate and H⁺, mediates drug sensitivity by regulating lactate metabolism. Targeting MCT1 has recently been regarded as a promising way to treat cancers and MCT1 Inhibitor has entered the clinical trial for GC treatment. However, the correlation of these two genes and their combined effects on chemotherapy sensitivity has not been clarified. In this study, we found that MACC1 and MCT1 were both highly expressed in GC and exhibited a positive correlation in clinical samples. Further, we demonstrated that MACC1 could mediate sensitivity of 5-FU and cisplatin in GC cells, and MACC1 mediated MCT1 regulation was closely related to this sensitivity. A MCT1 Inhibitor AZD3965 recovered the sensitivity of 5-FU and cisplatin in GC cells which overexpressed MACC1. These results suggested that MACC1 could influence the chemotherapy sensitivity by regulating MCT1 expression, providing new ideas and strategy for GC treatment.