Melatonin-induced ferroptosis in pancreatic cancer cells by stimulating endoplasmic reticulum stress and inhibiting alanine-serine-cysteine transporter 2-driven glutamine metabolism.

BACKGROUND

Pancreatic cancer, characterized by aggressive proliferation and metastasis, is a lethal malignancy. The nightly hormone melatonin serves as a rhythm-regulating hormone, and is used to treat different cancers including pancreatic cancer.

AIM

To investigate how melatonin acts against human pancreatic cancer cell lines and analyze the biological processes that cause the observed effects.

METHODS

Panc-1 and AsPC-1 cells were treated with melatonin. Cell viability was measured using the cell counting kit-8 assay. Western blotting and immunofluorescence were used to analyze protein expression levels. Ferroptosis was measured by analyzing lipid reactive oxygen species and malondialdehyde levels; apoptosis was assessed using flow cytometry.

RESULTS

Melatonin significantly inhibited the viability, colony formation, migration, and invasion of Panc-1 and AsPC-1 cells. Additionally, melatonin activated the endoplasmic reticulum (ER) stress pathway (protein kinase R-like ER kinase-eukaryotic initiation factor 2α-activating transcription factor 4), inhibited glutamine metabolism (alanine-serine-cysteine transporter 2-glutaminase 1-glutathione peroxidase 4, alanine-serine-cysteine transporter 2-glutathione peroxidase 4), and promoted ferroptosis in pancreatic cancer cells. Co-treatment with a high melatonin concentration and protein kinase R-like ER kinase agonist (CCT020312) enhanced melatonin-induced ferroptosis in pancreatic cancer cells. Melatonin demonstrated a variety of anticancer effects by inhibiting autophagy. This was achieved through the increased expression of sequestosome-1 and decreased expression of light chain 3. Additionally, melatonin facilitated the promotion of apoptosis.

CONCLUSION

Melatonin induces ferroptosis in pancreatic cancer cells by activating transcription factor 4-dependent ER stress and inhibiting glutamine metabolism, promotes apoptosis in pancreatic cancer cells, and inhibits autophagy, leading to synergistic anticancer effects.