Low-dose Simvastatin protects pancreatic cancer cells by promoting mitochondrial autophagy through TFEB

BACKGROUND: Pancreatic cancer is typically accompanied by fibrosis, forming a dense stromal matrix. This dense matrix restricts drug penetration, making it difficult for drugs to effectively reach tumor cells. Additionally, pancreatic cancer has inadequate local blood supply and "vascular irregularity," which makes it challenging for drugs to reach the core of the tumor. Even if some drugs reach the pancreas through systemic circulation, poor vascular permeability prevents them from effectively entering tumor cells, resulting in suboptimal therapeutic effects. Statins were initially used to treat high cholesterol levels and prevent cardiovascular diseases, but recent studies suggest that they may also have potential therapeutic effects on cancer, particularly certain types of cancer such as pancreatic cancer. However, clinical research on the use of statins for pancreatic cancer treatment is still ongoing, and the results are inconsistent. The effects of statins on pancreatic cancer may vary depending on the dose. Due to the aforementioned limitations of fibrosis and lack of blood supply in pancreatic cancer, simvastatin only exerts its effect on pancreatic cancer cells at low doses. PURPOSE: This study aimed to explore the effects of low-dose simvastatin on pancreatic cancer cells and the underlying mechanisms. We investigated the effects of different concentrations of simvastatin on pancreatic cancer cells. METHODS: The vitality of the cells was evaluated by CCK8, EDU staining, and the level of ferroptosis in pancreatic cancer cells was detected by flow cytometry detection of C11, MDA, ROS. RESULTS: We found that small doses of simvastatin can resist the toxicity of Erastin against pancreatic cancer cells. Under the transmission electron microscope, more mitophagosomes were produced in pancreatic cancer cells treated with small dose of simvastatin, and immunofluorescence revealed increased co-localization of lysosomes and mitochondria, indicating that simvastatin promoted the occurrence of mitophagy. At the same time, immunofluorescence confirmed that simvastatin promoted the nuclear translocation of TFEB, and chromatin immunoprecipitation and dual-luciferase gene report confirmed that TFEB is the transcription factor of P62/SQSTM1. This study clarified that a small dose of simvastatin, in the event of mitochondrial stress in pancreatic cancer cells, induces mitophagy to clear damaged mitochondria, protecting pancreatic cancer cells from ferroptosis and apoptosis, by promoting the transcription of P62/SQSTM1 through the nuclear translocation of TFEB. CONCLUSION: These findings may explain one of the reasons for the suboptimal efficacy of simvastatin in the treatment of pancreatic cancer, while also providing new insights for research on the antitumor effects of statins.