CDKN2A inhibited ferroptosis through activating JAK2/STAT3 pathway to modulate cisplatin resistance in cervical squamous cell carcinoma

Author:

Yong Xiang123,Zhang Yanling4,Tang Heng23,Hu Huaiyuan23,Song Rui23,Wu Qiang1

Affiliation:

1. Department of Pathology, The Second Affiliated Hospital of Anhui Medical University, Hefei City

2. Department of Pathology, Anhui Wanbei Coal-Electricity Group General Hospital

3. Department of Tumor Pathology, Suzhou City Key Laboratory of Tumor Pathology

4. Department of Oncology, Anhui Wanbei Coal-Electricity Group General Hospital, Suzhou City, Anhui Province, China

Abstract

Cervical squamous cell carcinoma (CESC) is a significant threat to women’s health. Resistance to cisplatin (DDP), a common treatment, hinders the therapeutic efficacy. Understanding the molecular basis of DDP resistance in CESC is imperative. Cyclin-dependent kinase inhibitor 2A (CDKN2A) expression was evaluated through quantitative real-time-PCR and western blot in clinical samples from 30 CESC patients and human cervical epithelial cells and CESC cell lines (SiHa, C33A, and Caski). It was also evaluated through bioinformatics analysis in Timer, Ualcan, and GEPIA database. Cell viability was detected by CCK-8. Apoptosis was detected by Calcein AM/PI assay. Lipid reactive oxygen species (ROS), malondialdehyde, glutathione, Fe2+, and iron level were detected by kits. Protein level of JAK2, STAT3, p-JAK2, p-STAT3, ACSL4, GPX4, SLC7A11, and FTL were detected by western blot. In CESC, elevated CDKN2A expression was observed. Cisplatin exhibited a dual effect, inhibiting cell proliferation and inducing ferroptosis in CESC. CDKN2A knockdown in a cisplatin-resistant cell line suppressed proliferation and induced ferroptosis. Moreover, CDKN2A was identified as an inhibitor of erastin-induced ferroptosis. Additionally, targeting the JAK2/STAT3 pathway enhanced ferroptosis in cisplatin-resistant cells. CDKN2A could inhibit ferroptosis in CESC through activating JAK2/STAT3 pathway to modulate cisplatin resistance.

Funder

Suzhou Health Research Project

Key Natural Science Project of Bengbu Medical University

Publisher

Ovid Technologies (Wolters Kluwer Health)

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