COL11A1 Inhibits Ferroptosis in Pancreatic Cancer by Regulating AKT/Beclin 1 Dependent Autophagy

Background: Collagen type XI alpha 1 (COL11A1) is overexpressed in pancreatic Cancer and is often associated with poor survival, chemoresistance, and tumor recurrence. However, the role of COL11A1 in pancreatic Cancer remains poorly understood.

Methods: We explored the correlation between COL11A1 and overall survival in pancreatic Cancer patients using Kaplan-Meier survival analysis and validated COL11A1's regulatory role in the viability of pancreatic Cancer cell line PANC-1 using Cell Counting Kit-8 and colony formation assays. To clarify the underlying mechanisms, we further examined COL11A1's modulation of Ferroptosis and Autophagy in PANC-1 cells by western blot, reverse transcription quantitative polymerase chain reaction (RT-qPCR), and immunofluorescence assays. Moreover, Autophagy agonist rapamycin, inhibitor 3-methyladenine (3-MA), and Akt/Beclin 1 pathway inhibitors were employed to dissect the regulatory crosstalk between COL11A1, Autophagy, and Ferroptosis.

Results: COL11A1 expression was negatively correlated with pancreatic Cancer patients' survival rate. Its overexpression significantly enhanced the viability and clonogenic capacity of erastin- and rapamycin-treated PANC-1 cells. Our data showed that COL11A1 reduced intracellular iron levels, suppressed Reactive Oxygen Species accumulation, downregulated malondialdehyde and microtubule-associated protein 1 light chain 3-II/I (LC3II/I) expression, while increasing glutathione (GSH), ferritin heavy chain 1 (FTH1) and solute carrier family 7 member 11 (SLC7A11) levels. Furthermore, COL11A1-mediated Ferroptosis inhibition was attenuated by the Autophagy agonist Rapamycin but enhanced by the inhibitor 3-MA. Notably, COL11A1 promoted Akt and Beclin 1 phosphorylation, and blocking the Akt/Beclin 1 pathway abrogated its ability to suppress Autophagy and Ferroptosis in pancreatic Cancer cells.

Conclusions: The study demonstrated that COL11A1 exerts its oncogenic effects by suppressing Autophagy via the Akt/Beclin 1 pathway, consequently inhibiting Ferroptosis in pancreatic Cancer cells. These findings reveal a novel molecular mechanism through which COL11A1 promotes tumor progression and provide a potential therapeutic target for pancreatic Cancer treatment.

AKT/Beclin 1 pathway; autophagy; collagen type XI alpha 1 chain; ferroptosis; pancreatic ductal carcinoma.