IRF1 inhibits temozolomide-induced senescence in glioblastoma cells via OAS2, offering a novel therapeutic target

Glioblastoma (GBM), an aggressive brain tumor, presents significant challenges due to poor treatment outcomes and high recurrence rates. Standard chemotherapy with Temozolomide (TMZ) often induces therapy-induced senescence (TIS) in GBM cells. While senescence can initially suppress tumors, accumulating evidence suggests that TIS, particularly through the senescence-associated secretory phenotype (SASP), can paradoxically drive tumor progression and relapse. Understanding the molecular mechanisms behind TMZ-induced senescence is crucial for developing strategies to overcome treatment resistance and improve patient prognosis.

Researchers investigated the role of interferon regulatory factor-1 (IRF1) in TMZ-induced senescence using GBM cells. They observed the expression of IRF1 in TMZ-treated senescent cells. Functional studies involved knockdown and overexpression of IRF1 to assess its impact on senescence markers, including senescence-associated β-galactosidase (SA-β-gal) activity, Lamin B1 protein expression, cell division, and SASP components. Further experiments explored the relationship between IRF1 and 2',5'-oligoadenylate synthetase 2 (OAS2) expression, and the effects of OAS2 knockdown on GBM cell senescence.

The study revealed that interferon regulatory factor-1 (IRF1) was consistently downregulated in TMZ-induced senescent GBM cells. Functional analyses demonstrated that knockdown of IRF1 significantly increased the activity of SA-β-gal, a key senescence marker, and reduced the protein expression of Lamin B1, which is often decreased in senescent cells. Furthermore, IRF1 knockdown inhibited cell division and enhanced the senescence-associated secretory phenotype (SASP) of GBM cells, collectively indicating that reduced IRF1 expression promotes cellular senescence. Conversely, overexpression of IRF1 partially reversed the TMZ-induced senescence phenotype. > Further mechanistic exploration identified 2',5'-oligoadenylate synthetase 2 (OAS2) as a crucial mediator: downregulation of IRF1 reduced OAS2 expression, while IRF1 overexpression increased OAS2. OAS2 itself was found to be downregulated in TMZ-induced senescent GBM cells, and its knockdown independently induced senescence in GBM cells.