Plitidepsin induces apoptosis in glioma cells through β-TrCP-mediated ubiquitination and degradation of BMI1.

Glioma remains a challenging malignancy with limited therapeutic options. This study investigates the antitumor efficacy and molecular mechanisms of plitidepsin, a marine-derived antitumor agent, in gliomas. In vitro experiments demonstrated that plitidepsin dose- and time-dependently inhibited viability and induced apoptosis in U87 and U251 glioma cells, accompanied by caspase-3 activation, cytochrome c/Smac release, and upregulation of the pro-apoptotic protein NOXA. Mechanistically, plitidepsin triggered intrinsic apoptosis by transcriptionally activating NOXA via suppression of BMI1, a polycomb repressor complex protein. Proteomic and functional studies revealed that plitidepsin promoted β-transducin repeat-containing protein (β-TrCP)-mediated K48-linked polyubiquitination and proteasomal degradation of BMI1, dependent on its conserved DSG(X)₂ + n(S) degron motif. Silencing BMI1 potentiated plitidepsin-induced apoptosis, while BMI1 overexpression conferred resistance. In vivo, plitidepsin significantly suppressed U87 xenograft tumor growth, correlating with reduced BMI1 expression, elevated NOXA levels, and decreased proliferation. These findings identify plitidepsin as a potent inducer of β-TrCP-dependent BMI1 degradation, unveiling a novel mechanism linking BMI1-NOXA axis activation to intrinsic apoptosis in gliomas. This study highlights plitidepsin's therapeutic potential for glioma treatment through targeting the ubiquitin-proteasome pathway.