Cancer research, 01 January 2019, Vol.79(1), pp.99-113
The DNA-methylating drug temozolomide, which induces cell death through apoptosis, is used for the treatment of malignant glioma. Here, we investigate the mechanisms underlying the ability of temozolomide to induce senescence in glioblastoma cells. Temozolomide-induced senescence was triggered by the specific DNA lesion O-methylguanine (OMeG) and characterized by arrest of cells in the G-M phase. Inhibitor experiments revealed that temozolomide-induced senescence was initiated by damage recognition through the MRN complex, activation of the ATR/CHK1 axis of the DNA damage response pathway, and mediated by degradation of CDC25c. Temozolomide-induced senescence required functional p53 and was dependent on sustained p21 induction. p53-deficient cells, not expressing p21, failed to induce senescence, but were still able to induce a G-M arrest. p14 and p16, targets of p53, were silenced in our cell system and did not seem to play a role in temozolomide-induced senescence. In addition to p21, the NF-κB pathway was required for senescence, which was accompanied by induction of the senescence-associated secretory phenotype. Upon temozolomide exposure, we found a strong repression of the mismatch repair proteins MSH2, MSH6, and EXO1 as well as the homologous recombination protein RAD51, which was downregulated by disruption of the E2F1/DP1 complex. Repression of these repair factors was not observed in G-M arrested p53-deficient cells and, therefore, it seems to represent a specific trait of temozolomide-induced senescence. SIGNIFICANCE: These findings reveal a mechanism by which the anticancer drug temozolomide induces senescence and downregulation of DNA repair pathways in glioma cells.
Ataxia Telangiectasia Mutated Proteins -- Metabolism ; Checkpoint Kinase 1 -- Metabolism ; Cyclin-Dependent Kinase Inhibitor P21 -- Metabolism ; DNA Repair -- Drug Effects ; DNA Repair Enzymes -- Antagonists & Inhibitors ; Glioblastoma -- Pathology ; Nf-Kappa B -- Metabolism ; Temozolomide -- Pharmacology
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