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.