Temozolomide induces senescence and repression of DNA repair pathways in glioblastoma cells via activation of ATR-CHK1, p21, and NF-kB

The DNA methylating drug temozolomide (TMZ), which induces cell death through apoptosis, is used for the treatment of malignant glioma. Here we investigate the mechanisms underlying the ability of TMZ to induce senescence in glioblastoma cells. TMZ-induced senescence was triggered by the specific DNA lesion O6MeG and characterized by arrest of cells in the G2/M phase. Inhibitor experiments revealed that TMZ-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. TMZ-induced senescence required functional p53 and was dependent on sustained p21 induction. p53-deficient cells failed to induce senescence but were still able to induce a G2/M arrest. p14 and p16, targets of p53, were silenced in our cell system, and did not seem to play a role in TMZ-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 (SASP). Upon TMZ exposure, we found a strong repression of the mismatch repair proteins MSH2, MSH6, and EXO1 as well as the homologous recombination protein RAD51, which were downregulated by disruption of the E2F1/DP1 complex. Repression of these repair factors was not observed in G2/M arrested p53-deficient cells and therefore represents a specific trait of TMZ-induced senescence.

https://ift.tt/2PSSRjW