p21-Dependent Senescence Induction by BMP4 Renders Glioblastoma Cells Vulnerable to Senolytics

Area of Science:

• Neuro-oncology
• Cellular senescence
• Cancer therapy

Background:

• Glioblastoma (GBM) exhibits significant cellular heterogeneity and plasticity.
• Bone morphogenetic protein 4 (BMP4) has therapeutic potential in GBM, but its role in senescence is unclear.
• Understanding BMP4's impact on GBM cell senescence is crucial for developing novel treatments.

Purpose of the Study:

• To investigate the ability of BMP4 to induce senescence in glioblastoma cells.
• To elucidate the role of p21 in BMP4-induced senescence.
• To evaluate the efficacy of senolytic agents in targeting BMP4-induced senescent GBM cells.

Main Methods:

• Primary GBM cultures were treated with BMP4.
• Senescence markers (cell size, p21 expression, senescence-related genes, β-galactosidase activity) were analyzed.
• A p21 knockout model and navitoclax treatment were employed to assess p21's role and senolytic efficacy.

Main Results:

• BMP4 induced senescence in GBM cells, especially mesenchymal-like (MES) GBM cells with high p21.
• p21 knockout significantly inhibited BMP4-induced senescence, preserving cell size and proliferation.
• Navitoclax effectively eliminated BMP4-induced senescent cells via apoptosis, sparing non-senescent cells.

Conclusions:

• BMP4 is a potent inducer of p21-dependent senescence in GBM, particularly in therapy-resistant MES-like cells.
• BMP4 exhibits context-dependent dual roles in differentiation and senescence.
• Targeting BMP4-induced senescence in MES-like GBM cells presents a promising therapeutic strategy for glioblastoma and potentially other cancers.