ΔNp63α Promotes Radioresistance in Esophageal Squamous Cell Carcinoma Through the PLEC-KEAP1-NRF2 Feedback Loop

Overview

Journal Cell Death Dis

Specialties Cell Biology
General Medicine

Date 2024 Nov 5

PMID 39500864

Authors

Jin Tao

Mian Mao

Yuhai Lu

Liyuan Deng

Shuhan Yu

Xiaofei Zeng

Weikun Jia

Zhiqiang Wu

Chenghua Li

Ruidong Ma

Hu Chen

Affiliations

Soon will be listed here.

Abstract

Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive cancers and is highly prevalent in China, exhibiting resistance to current treatments. ΔNP63α, the main isoform of p63, is frequently amplified in ESCC and contributes to therapeutic resistance, although the molecular mechanisms remain unknown. Here, we report that ΔNP63α is highly expressed in ESCC and is associated with radioresistance by reducing ROS level. Furthermore, ΔNP63α plays a critical role in radioresistance by directly transactivating the expression of PLEC. PLEC competitively interacts with KEAP1, resulting in the release of NRF2 from KEAP1 and its translocation from the cytosol to the nucleus, where it activates gene expression to facilitate ROS elimination. Additionally, radiotherapy-induced ROS also activates ΔNP63α expression via NRF2. Pharmacologic inhibition of NRF2 effectively improves radiosensitivity in nude mice. Collectively, our results strongly suggest that the ΔNp63α/PLEC/NRF2 axis plays a key role in radioresistance in ESCC, indicating that targeting NRF2 is a promising therapeutic approach for ESCC treatment.

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