PKCiota Inhibits the Ferroptosis of Esophageal Cancer Cells via Suppressing USP14-Mediated Autophagic Degradation of GPX4
Hao Tao, Sheng-Jie Song, Ze-Wen Fan, Wenting Li, Xin Jin, Wen Jiang, Jie Bai, Zhi‐Zhou Shi
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.