Abstract
Programmed death receptor-ligand 1 (PD-L1) plays a crucial role in immune evasion by tumour cells. Most tumour cells exhibit energy dependency and acquire energy from glycolysis. However, the relationship between glucose metabolism and PD-L1 expression remains unclear. In this study, changes in PD-L1 expression in renal carcinoma cells were evaluated during glucose deficiency and recovery, and PD-L1 could inversely regulate glycolysis. In addition, the possible signalling pathways activated by a low level of glucose to regulate PD-L1 were tested experimentally. The results showed that glucose deficiency could upregulate PD-L1 expression in two renal cancer cell lines, 786-O and OS-RC-2. Although the native levels of PD-L1 differed in the two cell lines, the upregulated PD-L1 expression was repristinated after glucose recovery. Moreover, epidermal growth factor receptor (EGFR) expression was upregulated in both cell lines with glucose deficiency. The use of an EGFR inhibitor reversed the upregulation of PD-L1 expression induced by glucose deficiency and inhibited the phosphorylation of extracellular regulated protein kinases 1 and 2 (ERK1/2). EGFR activated by epidermal growth factor (EGF) induced PD-L1 expression and ERK1/2 phosphorylation. Furthermore, an ERK1/2 inhibitor inhibited the phosphorylation of c-Jun and decreased the elevated PD-L1 expression induced by glucose deficiency. In addition, this study also showed that 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFK-2/FBPase 3 or PFKFB3) mediated upregulation of the level of glycolysis to improve the adverse environment through PD-L1 induction. Therefore, glucose metabolism can regulate the expression of PD-L1 through the EGFR/ERK/c-Jun pathway in renal cancer, and elevated PD-L1 can also regulate glycolysis by improving the expression of PFKFB3. The findings of this study could provide a new multiple target treatment for renal cell carcinoma (RCC) therapy.
Highlights
Renal cell carcinoma (RCC) is one of the most lethal types of urological cancer, accounting for approximately 4% of malignant tumours and approximately 3% of the mortality related to malignant tumours[1], but the Tumour-induced anergy may in part explain the low response rate[3]
Upon adding the optimal dose of gefitinib to the low-glucose culture medium, the upregulation of programmed death receptor-ligand 1 (PD-L1) was reversed after culture for 24 h (Fig. 4B). These results clearly showed that inhibiting epidermal growth factor receptor (EGFR) activation reduced the elevated expression of P-extracellular regulated protein kinases (ERKs), P-c-Jun and PD-L1 induced by glucose deficiency
We found that U0126 effectively inhibited the P-extracellular regulated protein kinases 1 and 2 (ERK1/2) activation induced by glucose deficiency and that the levels of P-ERK and P-c-Jun gradually decreased as the concentration of U0126 increased
Summary
Renal cell carcinoma (RCC) is one of the most lethal types of urological cancer, accounting for approximately 4% of malignant tumours and approximately 3% of the mortality related to malignant tumours[1], but the Tumour-induced anergy may in part explain the low response rate[3]. The mechanisms of immune dysfunction in cancer patients remain unclear. Under pathological conditions such as cancer, programmed death receptor-ligand 1 (PD-L1) expression is often. Yu et al Cell Death Discovery (2021)7:15 upregulated in tumour cells, and PD-L1 binds to programmed cell death protein 1 (PD-1) on T cells, resulting in potent immune suppression and tumour immune escape[4,5,6,7,8,9]. We tried to find the pathway underlying the high expression of PD-L1, which could be combined with an intervention focused on a target in that pathway to reduce the expression of PD-L1 to suppress tumour immune escape[13]. The expression of PD-L1 on tumours strongly correlates with the survival of cancer patients
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