Susceptibility of cervical cancer to dihydroartemisinin-induced ferritinophagy-dependent ferroptosis

Abstract

The clinical therapeutics of cervical cancer is limited due to the drug resistance and metastasis of tumor. As a novel target for antitumor therapy, ferroptosis is deemed to be more susceptible for those cancer cells with resistance to apoptosis and chemotherapy. Dihydroartemisinin (DHA), the primary active metabolites of artemisinin and its derivatives, has exhibited a variety of anticancer properties with low toxicity. However, the role of DHA and ferroptosis in cervical cancer remained unclear. Here, we showed that DHA could time-dependently and dose-dependently inhibit the proliferation of cervical cancer cells, which could be alleviated by the inhibitors of ferroptosis rather than apoptosis. Further investigation confirmed that DHA treatment initiated ferroptosis, as evidenced by the accumulation of reactive oxygen species (ROS), malondialdehyde (MDA) and liquid peroxidation (LPO) levels and simultaneously depletion of glutathione peroxidase 4 (GPX4) and glutathione (GSH). Moreover, nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy was also induced by DHA leading to subsequent increases of intracellular labile iron pool (LIP), exacerbated the Fenton reaction resulting in excessive ROS production, and enhanced cervical cancer ferroptosis. Among them, we unexpectedly found that heme oxygenase-1 (HO-1) played an antioxidant role in DHA-induced cell death. In addition, the results of synergy analysis showed that the combination of DHA and doxorubicin (DOX) emerged a highly synergistic lethal effect for cervical cancer cells, which was related also to ferroptosis. Overall, our data revealed the molecular mechanisms that DHA triggered ferritinophagy-dependent ferroptosis and sensitized to DOX in cervical cancer, which may provide novel avenues for future therapy development.

HPV prevalence and genotype distribution in 2,306 patients with cervical squamous cell carcinoma in central and eastern China

“…Our results also identified that the cases of HPV infection genotype and frequency were significantly lower in people under 30 than in other age groups, which is supported by the study of Fatima Mijit et al ( 27 ). This suggests that the lower positivity rate of HPV in women under 30 may be due to their higher immune levels ( 28 , 29 ). However, cases of advanced cervical cancer have also been reported in women under 30 years old in recent years ( 30 ).…”

Erastin induces ferroptosis in cervical cancer cells via Nrf2/HO-1 signaling pathway

“… 7 In addition, microRNA-660-5p has been shown to inhibit ferroptosis in SiHa cells, 23 while DHA can trigger ferritinophagy-dependent ferroptosis in SiHa cells. 24 Ferrostatin-1 is a specific ferroptosis inhibitor that prevents erastin-induced lipid ROS accumulation and inhibits ferroptosis in fibrosarcoma HT-1080 cells. 4 In the present work, ferrostatin-1 markedly diminished the suppressing activity of erastin on both HeLa and SiHa 24 cell growth, motility, and ROS production.…”

“… 24 Ferrostatin-1 is a specific ferroptosis inhibitor that prevents erastin-induced lipid ROS accumulation and inhibits ferroptosis in fibrosarcoma HT-1080 cells. 4 In the present work, ferrostatin-1 markedly diminished the suppressing activity of erastin on both HeLa and SiHa 24 cell growth, motility, and ROS production.…”

EPAS1, a hypoxia‐ and ferroptosis‐related gene, promotes malignant behaviour of cervical cancer by ceRNA and super‐enhancer

“… 25 Furthermore, ferroptosis is involved in the occurrence and development of cervical cancer and is related to its prognosis. 26 , 27 , 28 , 29 , 30 Some drugs exert therapeutic effects against cervical cancer through ferroptosis. 31 , 32 , 33 Hypoxia reduces Fenton chemistry and lipoxygenase activity, which are the key control systems for ferroptosis.…”