Correlation between levels of clock protein expression and effects on temozolomide-resistant glioblastoma and tumor progression.

in Human cell by Keng-Liang Kuo, Shu-Jyuan Chang, Aij-Lie Kwan, Chee-Yin Chai

TLDR

  • The study investigated the relationship between the circadian cycle and autophagic pathways in Glioblastoma and its TMZ chemoresistance counterpart, and found that NR1D1 might be a key player in TMZ chemoresistance.
  • High levels of NR1D1 might predict poor prognosis and shorter survival for GBM patients, but could also be used as a chemosensitizer for TMZ in these patients.
  • The study highlights the importance of considering the circadian cycle and autophagic pathways in the development of effective treatments for GBM.

Abstract

Glioblastoma (GBM) is the most common malignant intracranial neoplasm. Treatment with surgical resection and concurrent chemoradiotherapy may not achieve satisfactory results in life expectancy. Temozolomide (TMZ) chemoresistance is one of the most common reasons for treatment failure, but the role of the circadian cycle and autophagic pathways in this phenomenon is unknown. This study investigated the relationship between the circadian cycle and autophagic pathways in GBM and its TMZ chemoresistance counterpart. The predictive potential of NR1D1 and MGMT was analyzed by using 631 glioma cases derived from the TCGA GBM dataset. Human GBM cell lines (U-87 MG, GBM 8401) and their TMZ chemoresistance counterparts were used for MGMT, circadian proteins (CLOCK, BMAL1, NR1D1), and LC3B analysis. In addition, immunohistochemical staining for NR1D1 was performed in 78 GBM samples, and the results were analyzed with patients' clinicopathological parameters. Results revealed a decrease in NR1D1 expression in GBM cells which could enhance TMZ chemosensitivity. Different expressions of autophagic markers were also noted in GBM cell lines with and without TMZ chemoresistance, indicating a significant role for NR1D1 in TMZ chemoresistance in the GBM cell line. In addition, higher expression of NR1D1 in tumor samples was correlated with poor prognosis and shorter survival. In conclusion, high levels of NR1D1 not only could predict poor prognosis but it could also be used as a chemosensitizer for TMZ in GBM patients.

Overview

  • The study aimed to investigate the predictive potential of NR1D1 and MGMT genes in glioma cases and their role in TMZ chemoresistance.
  • The study used 631 glioma cases derived from the TCGA GBM dataset, as well as human GBM cell lines (U-87 MG, GBM 8401) and their TMZ chemoresistance counterparts to analyze MGMT, circadian proteins (CLOCK, BMAL1, NR1D1), and LC3B.

Comparative Analysis & Findings

  • The study revealed a decrease in NR1D1 expression in GBM cells, which could enhance TMZ chemosensitivity.
  • Different expressions of autophagic markers were noted in GBM cell lines with and without TMZ chemoresistance, indicating a significant role for NR1D1 in TMZ chemoresistance in the GBM cell line.
  • Higher expression of NR1D1 in tumor samples was correlated with poor prognosis and shorter survival.

Implications and Future Directions

  • High levels of NR1D1 not only could predict poor prognosis but it could also be used as a chemosensitizer for TMZ in GBM patients.
  • Future studies could investigate the molecular mechanisms underlying the role of NR1D1 in TMZ chemoresistance and explore its potential as a therapeutic target.
  • The study highlights the importance of considering the circadian cycle and autophagic pathways in the development of effective treatments for GBM.
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