Osthole inhibits proliferation and induces autophagy-dependent ferroptosis of cervical cancer cells through induction of TFR1
Osthole (OST), a natural coumarin, exerts its anticancer effects by inducing cancer cell necroptosis, apoptosis, pyroptosis or autophagy. In He La cells, OST cause mitochondrial atrophy, increased membrane density and reduced cristae, which are characteristics of ferroptosis. However, the mechanisms of OST-induced ferroptosis in cervical cancer cells remain unclear. In the present study, we found that OST inhibited He La cells' proliferation which triggered ferroptosis. Further studies showed that ferroptosis or autophagy inhibition could reverse the inhibitory effects of OST on He La cell proliferation, and significantly inhibited ferroptosis and autophagy induced by OST. Moreover, autophagy stimulation enhanced the ferroptosis induction of OST, while ferroptosis induction in turn enhanced the autophagy levels caused by OST. Furthermore, Transferrin Receptor 1 (TRF-1) silencing effectively reduced OST-induced ferroptosis and autophagy, while TFR1 overexpression notably enhanced OST-induced ferroptosis and autophagy in He La cells. In addition, animal experiments demonstrated that overexpression of TFR1 effectively suppressed tumor growth in cervical cancer He La cells, and its expression was associated with the activation of ferroptosis and autophagy. In conclusion, our study revealed the detailed mechanism of OST-induced He La cells ferroptosis and autophagy, and the association between autophagy and ferroptosis in OST-induced cell death.