Expression of LASS2 Can be Regulated by Dihydroartemisinin to Regulate Cisplatin Chemosensitivity in Bladder Cancer Cells

Abstract

Introduction: The aim of this study was to investigate the potential of dihydroartemisinin to augment the efficacy of cisplatin chemotherapy through the modulation of LASS2 expression.

Methods: TCMSP, CTR-DB, TCGA-BLC, and other databases were used to analyze the possibility of LASS2 as the target gene of dihydroartemisinin. Cell experiments revealed the synergistic effect of DDP and DHA. Animal experiments showed that DHA inhibited the growth of DDP-treated mice. In addition, WB, real-time PCR, and immunohistochemical analysis showed that DHA enhanced LASS2 (CERS2) expression in bladder cancer cells and DDP-treated mice.

Results: LASS2 is associated with cisplatin chemosensitivity.LASS2 expression levels are different between BLC tissues and normal tissues. COX analysis showed that patients with high LASS2 expression had a higher cumulative overall survival rate than those with low LASS2 expression. The Sankey plot showed that LASS2 expression is lower in BLC tissues with more advanced stage and distant metastasis. The docking score of DHA and LASS2 reached the maximum value of -5.5259, indicating that DHA had a strong binding affinity with LASS2 targets. CCK8 assay showed that the most effective concentration ratio of DHA to DDP was 2.5μg/ml + 10μg/ml. In vivo experiments showed that DHA inhibited tumor growth in cisplatin-treated mice. In addition, WB, RT-qPCR, and immunohistochemical analysis showed that DHA was able to enhance LASS2 expression in BLC cells and DDP-treated mice.

Conclusion: The upregulation of LASS2 (CERS2) expression in bladder cancer cells by DHA has been found to enhance cisplatin chemosensitivity.

Keywords: Dihydroartemisinin; bladder cancer; ceramide synthase 2; cisplatin.