Temozolomide-induced senescent glioblastoma cells acquire sensitivity to TRAIL death receptor 5-mediated apoptosis

Area of Science:

• Oncology
• Cellular Biology
• Cancer Therapeutics

Background:

• Therapy-induced senescence is a critical factor in cancer treatment, often leading to drug resistance.
• Senolytics, drugs that eliminate senescent cells, offer potential new therapeutic strategies for cancer.
• Glioblastoma (GBM) presents significant treatment challenges due to its aggressive nature and resistance mechanisms.

Purpose of the Study:

• To investigate the apoptotic potential of the DR5 receptor agonist, DR5-B, in temozolomide (TMZ)-induced senescent glioblastoma cells.
• To evaluate the sensitization effect of TMZ-induced senescence on glioblastoma cells to DR5-B-mediated apoptosis.
• To analyze the molecular and cellular changes associated with senescence in glioblastoma and their impact on therapeutic response.

Main Methods:

• Induction of senescence in U87MG and T98G glioblastoma cell lines and primary patient-derived GBM samples using TMZ.
• Characterization of senescence features, including cell size, nuclear morphology, β-galactosidase activity, p21 expression, and lipofuscin autofluorescence.
• Metabolic profiling using fluorescence lifetime imaging (FLIM) of NADH to assess metabolic shifts.
• Analysis of gene expression related to apoptosis, inflammation, DNA metabolism, and cell cycle.
• Assessment of apoptosis induction by DR5-B in senescent and non-senescent glioblastoma cells.

Main Results:

• TMZ-induced senescence was most prominent in p53-proficient, MGMT-deficient U87MG cells, characterized by distinct morphological and molecular markers.
• Senescent U87MG cells exhibited a metabolic shift towards glycolysis and an upregulation of DR5, DcR1, DcR2, and cFLIP.
• Pre-treatment with TMZ significantly sensitized U87MG cells to DR5-B-mediated apoptosis, while T98G cells showed limited response.
• Differential gene expression in TMZ-treated U87MG cells revealed activated pro-inflammatory and pro-apoptotic signaling pathways.
• Two out of three patient-derived GBM samples demonstrated similar senescence induction and sensitization to DR5-B after TMZ pre-treatment.

Conclusions:

• TMZ-induced senescence enhances glioblastoma cell sensitivity to DR5 receptor agonists like DR5-B.
• The heterogeneous response of glioblastoma cells to senescence induction highlights the need for personalized therapeutic strategies.
• Targeting therapy-induced senescence may represent a viable approach for developing novel senolytic therapies against glioblastoma.