TMEM105 modulates disulfidptosis and tumor growth in pancreatic cancer via the β-catenin-c-MYC-GLUT1 axis.

Abstract

Background: Pancreatic cancer (PCa) is one of the most malignant diseases in the world. Different from ferroptosis and apoptosis, disulfidptosis is a novel type of cell death. The role of disulfidptosis in PCa remains uncovered. Methods: Disulfidptosis-related lncRNAs were identified based on TCGA-PAAD database. The disulfidptosis-related predict signature was constructed and verified by bioinformatic analysis. TCGA and GTEx database and Renji tissue microarray (TMA) were applied to determine TMEM105 and its clinical significance. F-actin and PI staining were performed to detect disulfidptosis of PCa cells. The biological function of TMEM105 was investigated by loss-of-function and gain-of-function assays. RNA pull-down and LC-MS/MS analysis were employed to detect TMEM105 interacted proteins. The tissue samples from PCa patients with PET-CT information were utilized to validate the TMEM105-β-catenin-c-MYC-GLUT1 pathway in clinical settings. Results: A disulfidptosis-related predict signature, which was comprised of six lncRNAs, was constructed and validated by bioinformatic analysis. TMEM105 was identified as disulfidptosis-related lncRNA whose high expression predicted a poor prognosis in PCa. Functional studies revealed that TMEM105 promoted the growth and mitigated the disulfidptosis in PCa. Mechanically, TMEM105 upregulated the expression of β-catenin by maintaining the protein stability through the proteosome pathway. The forced expressed β-catenin increased the expression of glycolysis-related transcription factor c-MYC, thus induced the transcription activity of GLUT1. Conclusion: These results revealed the growth acceleration and the disulfidptosis mitigation function of TMEM105 in PCa. Targeting the TMEM105-β-catenin-c-MYC-GLUT1 pathway could be a potent therapy for PCa patients.