MiR-1253 Potentiates Cisplatin Response in Pediatric Group 3 Medulloblastoma by Regulating Ferroptosis

Abstract

Medulloblastomas (MB) are the most common malignant pediatric brain tumor and a leading cause of childhood mortality. Aggressive tumors belonging to group 3 (G3MB) are distinguished by a marked reduction in programmed cell death by ferroptosis. These aggressive tumors also enrich iron transport and glutathione metabolism. A highly enriched pathway in these tumors is iron-sulfur (Fe-S) cluster binding corresponding to significant upregulation of ABCB7, a poor prognostic feature linked with accelerated mortality. This study elucidated whether repressing ABCB7 activates ferroptosis to mitigate G3MB aggressiveness and whether this pathway is pharmacologically targetable. In silico and in vitro analyses confirmed upregulation of ABCB7 and GPX4, the central regulator of ferroptosis, in G3MB cell lines and tumors. Repressing ABCB7 (miR-1253OE, siABCB7, sh-ABCB7) induced iron overload, elicited oxidative stress, and triggered lipid peroxidation, leading to an abrogation of medullosphere formation and cell death by ferroptosis. Intriguingly, fractionation studies revealed that ABCB7 repression abrogated GPX4 expression, most likely by GSH depletion. Repressing ABCB7 induced mitochondrial dysfunction and reduced oxidative phosphorylation. Cisplatin, a chemotherapeutic mainstay of G3MB, induces cell death by DNA crosslinking. In ABCB7 repressed cell lines, the IC50 of cisplatin was halved, resulting in augmented oxidative stress and lipid peroxidation, culminating in a higher index of ferroptosis. Artesunate, an anti-malarial drug capable of triggering ferroptosis, was shown to synergize with cisplatin, reducing tumor burden and significantly prolonging survival. Taken together, the current study illustrates how targeting iron transport can augment ferroptosis in G3MBs. It further identifies an FDA-approved drug capable of recapitulating these effects and potentiating mainstay chemotherapy.