SLC45A4 Promotes Glycolysis and Prevents AMPK/ULK1-induced Autophagy in TP53 Mutant Pancreatic Ductal Adenocarcinoma.

Background Somatic mutations of the TP53 gene occur frequently in pancreatic ductal adenocarcinoma (PDA). The solute carrier family 45 member A4 (SLC45A4) is a H+ - dependent sugar cotransporter. The role of SLC45A4 in PDA, especially in TP53 mutant PDA, remains poorly understood. Methods We explored the TCGA datasets to identify oncogenes in TP53 mutant PDA. MTS, colony formation and Edu assays were performed to study the function of SLC45A4 in vitro. Glucose consumption, lactate production and ATP production were detected to evaluate glucose utilization. The ECAR and the OCR assay were used to evaluate glycolysis and oxidative phosphorylation. The subcutaneous xenotransplantation models were conducted to explore the function of SLC45A4 in vivo. RNA-seq and GSEA were employed to explore the biological alteration caused by SLC45A4 knockdown. Western blot was performed to evaluate the activation of glycolysis, AMPK pathway and autophagy. Results SLC45A4 was overexpressed in PDA and whose expression was significantly higher in TP53 mutant PDA than that in wildtype PDA tissues. Moreover, high level of SLC45A4 expression was tightly associated with poor clinical outcomes in PDA patients. Silencing SLC45A4 inhibited proliferation in TP53 mutant PDA cells. Knockdown of SLC45A4 reduced glucose uptake and ATP production which led to activation of autophagy via AMPK/ULK1 pathway. Deleting SLC45A4 in TP53 mutant HPAF-II cells inhibited the growth of xenografts in nude mice. Conclusion Our study found that SLC45A4 prevents autophagy via AMPK/ULK1 axis in TP53 mutant PDA, which may be a promising biomarker and therapeutic target in TP53 mutant PDA.