Targeting ARNT Attenuates Chemoresistance Through Destabilizing P38α-MAPK Signaling in Glioblastoma

Overview

Journal Cell Death Dis

Specialties Cell Biology
General Medicine

Date 2024 May 28

PMID 38806469

Authors

Wahafu Alafate

Gen Lv

Jiantao Zheng

Haiping Cai

Wei Wu

Yong Yang

Shichao Du

Dong Zhou

Peng Wang

Affiliations

Soon will be listed here.

Abstract

Glioblastoma (GBM) is the most aggressive and lethal brain tumor in adults. This study aimed to investigate the functional significance of aryl hydrocarbon receptor nuclear translocator (ARNT) in the pathogenesis of GBM. Analysis of public datasets revealed ARNT is upregulated in GBM tissues compared to lower grade gliomas or normal brain tissues. Higher ARNT expression correlated with the mesenchymal subtype and poorer survival in GBM patients. Silencing ARNT using lentiviral shRNAs attenuated the proliferative, invasive, and stem-like capabilities of GBM cell lines, while ARNT overexpression enhanced these malignant phenotypes. Single-cell RNA sequencing uncovered that ARNT is highly expressed in a stem-like subpopulation and is involved in regulating glycolysis, hypoxia response, and stress pathways. Mechanistic studies found ARNT activates p38 mitogen-activated protein kinase (MAPK) signaling to promote chemoresistance in GBM cells. Disrupting the ARNT/p38α protein interaction via the ARNT PAS-A domain restored temozolomide sensitivity. Overall, this study demonstrates ARNT functions as an oncogenic driver in GBM pathogenesis and represents a promising therapeutic target.

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