Cdc25A inhibits autophagy-mediated ferroptosis by upregulating ErbB2 through PKM2 dephosphorylation in cervical cancer cells

Cervical cancer is the leading cause of cancer-related deaths in women, and treatment for cervical cancer is very limited. Emerging evidence suggests that targeting ferroptosis is a promising way to treat cancer. Here, we investigated the role of ferroptosis in cervical cancer, with a focus on the C...

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Published in:	Cell death & disease 2021-11, Vol.12 (11), p.1055-14, Article 1055
Main Authors:	Wang, Chen, Zeng, Jie, Li, Li-Jie, Xue, Min, He, Si-Li
Format:	Article
Language:	eng
Subjects:	Animals Autophagy Autophagy - drug effects Autophagy - genetics Carrier Proteins - metabolism cdc25 Phosphatases - genetics cdc25 Phosphatases - metabolism Cell Line, Tumor Cell viability Cervical cancer Cervix Dephosphorylation ErbB-2 protein ErbB-3 protein Female Ferroptosis - drug effects Ferroptosis - genetics Fluorescence microscopy Gene Expression Regulation, Neoplastic - drug effects Humans Male Membrane Proteins - metabolism Mice Mice, Nude Phagocytosis Phosphorylation - drug effects Receptor, ErbB-2 - genetics Receptor, ErbB-2 - metabolism RNA, Messenger - genetics RNA, Messenger - metabolism Signal Transduction - drug effects Sorafenib - pharmacology Thyroid Hormone-Binding Proteins Thyroid Hormones - metabolism Transcription Tumors Up-Regulation - drug effects Uterine Cervical Neoplasms - genetics Uterine Cervical Neoplasms - pathology Xenografts
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Summary:	Cervical cancer is the leading cause of cancer-related deaths in women, and treatment for cervical cancer is very limited. Emerging evidence suggests that targeting ferroptosis is a promising way to treat cancer. Here, we investigated the role of ferroptosis in cervical cancer, with a focus on the Cdc25A/PKM2/ErbB2 axis. Cervical cancer cells were treated with sorafenib to induce ferroptosis. Cellular MDA/ROS/GSH/iron detection assays were used to measure ferroptosis. MTT assays were performed to assess cell viability. qRT-PCR, western blot, and immunostaining assays were performed to measure the levels of proteins. Autophagy was monitored by fluorescence microscopy. Nuclear and cytosolic fractions were isolated to examine the location of PKM2 modifications. Co-IP experiments were conducted to determine the Cdc25A/PKM2 interaction. ChIP assays were performed to measure the binding affinity between H3K9Ac and the ErbB3 promoter, and a dual luciferase assay was performed to examine the transcriptional activity of ErbB2. A nude mouse xenograft model was used to examine the effects of the Cdc25A/ErbB2 axis on tumour growth in vivo. Cdc25A was elevated in human cervical cancer tissues but was reduced during sorafenib-induced ferroptosis of cervical cancer cells. Overexpression of Cdc25A inhibited sorafenib-induced ferroptosis by dephosphorylating nuclear PKM2 and suppressing autophagy. Cdc25A regulated autophagy-induced ferroptosis by increasing ErbB2 levels via the PKM2-pH3T11-H3K9Ac pathway. Cdc25A increased the resistance of cervical cancer to sorafenib, while knockdown of ErbB2 blocked these effects. Cdc25A suppressed autophagy-dependent ferroptosis in cervical cancer cells by upregulating ErbB2 levels through the dephosphorylation of PKM2. These studies revealed that Cdc25A/PKM2/ErbB2 pathway-regulated ferroptosis could serve as a therapeutic target in cervical cancer.
ISSN:	2041-4889 2041-4889