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Background: Pancreatic ductal adenocarcinoma (PDAC) is a form of cancer known for its aggressive behavior, poor survival rates, and high resistance to chemotherapy. Our previous study has found that low calcium-activated chloride channel regulator 1 (CLCA1) expression is associated with worse survival of patients with PDAC, yet its underlying function in PDAC is not clear.
Methods: We constructed CLCA1-overexpressed Pancreatic Adenocarcinoma Cell Line 1 (PANC-1) cells and in-vestigated its effect on the cell growth and invasion by Cell Counting Kit-8 (CCK-8) Assay and Transwell Migration Assay. Sensitivity of PANC-1 cells to gemcitabine and hypoxia environment was also studied. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) based-proteomics was employed to discover key molecular cause based on CLCA1-overexpression. Further mechanistic insights into the SIRT1/HIF-1α axis were obtained using Ribonucleic Acid (RNA) interference, qPCR, and western blotting.
Results: CLCA1 expression was significantly reduced in PANC-1 cells. Overexpression of CLCA1 inhibited proliferation and invasion while enhancing sensitivity to gemcitabine. Proteomic study suggested that SIRT1 expression was dramatically downregulated in CLCA1-over expression PANC-1 cells compared with control PANC-1 cells. Mechanistic studies revealed that CLCA1 downregulates SIRT1 expression, leading to reduced stabilization of HIF-1α and subsequent suppression of its downstream hypoxia-responsive genes (GLUT1, LDHA). Hypoxia partially reversed this suppression. Synergistic effects were observed with CLCA1 overexpression and SIRT1 knockdown, significantly reducing tumor cell proliferation and HIF-1α expression.
Conclusions: We found that CLCA1 modulates the SIRT1/HIF-1α pathway, suppressing tumor proliferation, and might enhance gemcitabine sensitivity in pancreatic cancer cells. This investigation points to CLCA1 as a viable therapeutic target for tackling hypoxia-induced chemoresistance and enhancing treatment success in PDAC. Further exploration of CLCA1-based therapies could offer new opportunities for clinical translation.
DOI: 10.7754/Clin.Lab.2025.250721
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