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

Mar 24, 2025Human cell

Links between daily rhythm protein levels and growth in drug-resistant brain tumors

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Circadian Biology on OpenScience ↗PubMed ↗DOI ↗

Abstract

Analysis of 631 glioma cases shows that high levels of NR1D1 may predict poor prognosis in glioblastoma patients.

Decreased NR1D1 expression in glioblastoma cells may enhance sensitivity to temozolomide (TMZ).
Expression levels of autophagic markers differ between TMZ-sensitive and TMZ-resistant glioblastoma cell lines.
High NR1D1 expression in tumor samples is associated with shorter survival rates in patients.
The relationship between circadian cycle, autophagic pathways, and TMZ chemoresistance in glioblastoma remains unclear.

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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.

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

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