The Expression And Significance Of Monocarboxylate Transporter In T Cell Lymphomas And The Preliminary Explore Of The Inhibition Effect

T-cell lymphoma(TCL),a highly heterogeneous and aggressive malignant lymphoproliferative disease,accounts for about 25% to 30% of non-Hodgkin’s lymphoma(NHL)in China.The disease characterized with rapid progression,short survival time,unsatisfactory overall efficacy of conventional first-line chemotherapy,and frequent transition to relapse/refractory.In recent years,a variety of new drugs involving TCL therapy have been developed continuously,but the improvement of prognosis is still limited.Therefore,there is an urgent need to explore more new therapeutic pathways and potential targets,while the energetic metabolism of cancer drawn our attention.Tumor cells preferentially consume glucose to generate lactate by anaerobic glycolysis rather than oxidative phosphorylation,although in the aerobic environment,a phenomenon known as the Warburg effect.Two subtypes of monocarboxylate transporter(MCT),MCT1 and MCT4,are critical symporters mediating lactate efflux and preventing intracellular acidification during tumor growth.Numerous domestic and abroad studies have elucidated the expression of MCT1 and MCT4 in various tumors,and part of them also involved the effect of inhibiting MCT1/MCT4 as treatment.However,their role in TCL is barely reported.The purpose of this study was to reveal the expression and prognostic value of MCT1/MCT4 in TCL patients,and to determine the effect of AZD3965,a selective inhibitor of MCT1,on TCL cell line in vitro,and investigate its possibility as a potential therapeutic target for TCL.Study objects and methods :(1)The expression levels of SLC16A1(MCT1)and SLC16A3(MCT4)genes in normal tissues and TCL cell lines were analyzed by inquiring in relevant databases.(2)Peripheral blood lymphocytes were collected from TCL patients,and the expression of MCT1 and MCT4 genes and proteins were detected by RT-PCR and Western blot.(3)Pathological sections of TCL patients were collected,and the expression of MCT1 and MCT4 proteins in tumor tissues was analyzed by immunohistochemistry,and the prognosis value was compared between patients with high and low expression levels of MCT1/MCT4 according to clinical laboratory and follow-up data.(3)TCL cell line Hu T-102 and SUP-T1 cells were cultured.(4)Hu T-102 and SUP-T1 cells were incubated with gradient concentrations of AZD3965.The effects of AZD3965 on cell proliferation and apoptosis were examined using cell proliferation assay.The changes of lactate and lactate dehydrogenase(LDH)levels following times were detected after the inhibition,and cell apoptosis was detected by flow cytometry.The results showed that :(1)the expression levels of MCT1 and MCT4 gene and protein in peripheral blood lymphocytes of TCL patients were significantly higher than those of healthy controls.(2)The expression of MCT1 and MCT4 genes in peripheral blood lymphocytes of TCL patients was significantly higher than that in the controls,and the expression of MCT1 protein was increased,but there was no significant difference in MCT4 protein.(3)The protein expression levels of MCT1 and MCT4 in TCL patients were significantly higher than those in the control group.(3)Overall survival(OS)and progression-free survival(PFS)in TCL patients with high MCT1 expression were significantly shorter than those in the low MCT1 expression group,while there were no significant differences in OS and PFS between the high and low MCT4 expression groups.(4)After AZD3965 was added,the viability of Hu T-102 and SUP-T1 cells declined,and the effects enhanced with AZD3965 concentration elevated.(5)After adding AZD3965,the levels of intracellular lactate and LDH of Hu T-102 and SUP-T1 cells were higher than those in control.(6)Apoptosis of SUP-T1 cells was enhanced by AZD3965 treatment.In conclusion,the expression of MCT1 and MCT4 in TCL is up-regulated,and the high expression of MCT1 may be a risk factor for the prognosis of patients.In vitro cell experiments showed that AZD3965,a selective inhibitor of MCT1,could cause lactate accumulation intracellularly in TCL cells,reduce the cell viability at a certain concentration,and induce cell apoptosis.MCT1 may be a therapeutic target for TCL,but further preclinical trials are required.