Antidepressants Fluoxetine Mediates Endoplasmic Reticulum Stress and Autophagy of Non–Small Cell Lung Cancer Cells Through the ATF4-AKT-mTOR Signaling Pathway

Fluoxetine, one of the latest clinical antidepressants, is reported to have the anti-proliferative effect on cancer cells via immune-related pathways. However, the mechanism is still not known. This study mainly focused on the discovery of the molecular basis of the inhibitory effect of fluoxetine in lung cancer. The specific anti-proliferation effect and autophagy induced by fluoxetine on lung cancer cell were shown in CCK8 and immunofluorescence. The RNA sequence hinted that the endoplasmic reticulum (ER) stress-related protein and mTOR pathway were enriched after fluoxetine treatment. Western blot results revealed that the ER stress pathway was activated by fluoxetine, including PERK, ATF4, and CHOP, while the AKT/mTOR pathway was inhibited. In addition, the transfection of ATF4 siRNA further discovered that ER stress participated in the inhibition of AKT/mTOR pathway and the induction of anti-proliferation and autophagy in the fluoxetine-treated cells. More importantly, fluoxetine was demonstrated to play cytotoxic activity in cancer cells without affecting normal cells. Our results showed that fluoxetine triggered the ATF4-AKT-mTOR signaling pathway to induce cell cycle arrest and autophagy restraining cancer cells’ growth in lung cancer. This study found fluoxetine unaffected the proliferation of normal lung epithelial cells, providing safe clinical therapeutic strategies for lung cancer patients with depression.