PKCiota Inhibits the Ferroptosis of Esophageal Cancer Cells via Suppressing USP14-Mediated Autophagic Degradation of GPX4
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Published:2024-01-17
Issue:1
Volume:13
Page:114
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ISSN:2076-3921
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Container-title:Antioxidants
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language:en
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Short-container-title:Antioxidants
Author:
Tao Hao1,
Song Sheng-Jie1,
Fan Ze-Wen1,
Li Wen-Ting1,
Jin Xin1,
Jiang Wen2,
Bai Jie1,
Shi Zhi-Zhou1
Affiliation:
1. Medical School, Kunming University of Science and Technology, Kunming 650500, China
2. Department of Thoracic Surgery, The First People’s Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming 650000, China
Abstract
Esophageal squamous cell carcinoma (ESCC) is one of the most frequent malignant tumors, and the mechanisms underlying the anti-ferroptosis of esophageal cancer cells are still largely unclear. This study aims to explore the roles of amplified protein kinase C iota (PKCiota) in the ferroptosis of ESCC cells. Cell viability, colony formation, MDA assay, Western blotting, co-IP, PLA, and RNA-seq technologies are used to reveal the roles and mechanisms underlying the PKCiota-induced resistance of ESCC cells to ferroptosis. We showed here that PKCiota was amplified and overexpressed in ESCC and decreased during RSL3-induced ferroptosis of ESCC cells. PKCiota interacted with GPX4 and the deubiquitinase USP14 and improved the protein stability of GPX4 by suppressing the USP14-mediated autophagy–lysosomal degradation pathway. PKCiota was negatively regulated by miR-145-5p, which decreased in esophageal cancer, and also regulated by USP14 and GPX4 by a positive feedback loop. PKCiota silencing and miR-145-5p overexpression suppressed tumor growth of ESCC cells in vivo, respectively; even a combination of silencing PKCiota and RSL3 treatment showed more vital suppressive roles on tumor growth than silencing PKCiota alone. Both PKCiota silencing and miR-145-5p overexpression sensitized ESCC cells to RSL3-induced ferroptosis. These results unveiled that amplified and overexpressed PKCiota induced the resistance of ESCC cells to ferroptosis by suppressing the USP14-mediated autophagic degradation of GPX4. Patients with PKCiota/USP14/GPX4 pathway activation might be sensitive to GPX4-targeted ferroptosis-based therapy.
Funder
National Natural Science Foundation of China
Joint Medical Program of Kunming University of Science and Technology
Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences
innovation team of oxidative stress and defense of Yunnan Province
Yunnan (Kunming) Zhou Demin Expert Workstation Project
Subject
Cell Biology,Clinical Biochemistry,Molecular Biology,Biochemistry,Physiology