Abstract
Malignant brain tumors are responsible for catastrophic morbidity and mortality globally. Among them, glioblastoma multiforme (GBM) bears the worst prognosis. The GrpE-like 2 homolog (GRPEL2) plays a crucial role in regulating mitochondrial protein import and redox homeostasis. However, the role of GRPEL2 in human glioblastoma has yet to be clarified. In this study, we investigated the function of GRPEL2 in glioma. Based on bioinformatics analyses from the Cancer Gene Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA), we inferred that GRPEL2 expression positively correlates with WHO tumor grade (p < 0.001), IDH mutation status (p < 0.001), oligodendroglial differentiation (p < 0.001), and overall survival (p < 0.001) in glioma datasets. Functional validation in LN229 and GBM8401 GBM cells showed that GRPEL2 knockdown efficiently inhibited cellular proliferation. Moreover, GRPEL2 suppression induced cell cycle arrest at the sub-G1 phase. Furthermore, GRPEL2 silencing decreased intracellular reactive oxygen species (ROS) without impending mitochondria membrane potential. The cellular oxidative respiration measured with a Seahorse XFp analyzer exhibited a reduction of the oxygen consumption rate (OCR) in GBM cells by siGRPEL2, which subsequently enhanced autophagy and senescence in glioblastoma cells. Taken together, GRPEL2 is a novel redox regulator of mitochondria bioenergetics and a potential target for treating GBM in the future.
Highlights
Over the past century, the treatment of malignant tumors of the brain has remained a critical challenge
According to the study of Srivastava, we proposed that the human nucleotide exchange factor (NEF) paralog, GrpE-like 2 homolog (GRPEL2), is responsible for tumorigenesis mediated by oxidative stress through mitochondrial heat shock protein (mt-HSP) machinery [6]
Upon subdividing the tumor groups in the the Cancer Gene Atlas (TCGA) dataset (GBMLGG) into Grade-II (n = 225), Grade-III (n = 272), and GradeIV (n = 165), based on the WHO’s classification, we demonstrated that GRPEL2 mRNA
Summary
The treatment of malignant tumors of the brain has remained a critical challenge. Recurrence occurs in 90% of the patients after primary treatment. One cause of this poor consequence is the development of the multidrug-resistance (MDR) phenotypes, making prognosis frustrating [1,2,3]. Glioma cells that rely on glycolytic metabolism readily adapt to bioenergetic stressors by engaging their mitochondrial pathway to survive and grow efficiently [10]. This observation suggests that the mitochondrial function plays an essential and promising role in the oncobiology of gliomas [1,11,12]
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