Repressing ABCB7 Potentiates Cisplatin Response in Pediatric Group 3 Medulloblastoma by Triggering Ferroptosis

Abstract Medulloblastomas (MB), the most common malignant pediatric brain tumor and a leading cause of childhood mortality, are stratified into four primary subgroups. Deletions within chromosomal locus 17p13.3, which houses multiple tumor suppressor genes including miR-1253, characterize high-risk group 3 tumors. These aggressive tumors also enrich iron transport genes to satisfy their high proliferative need. MiR-1253 targets iron transport by inhibiting the mitochondrial Fe-S transporter, ABCB7. This study elucidated the impact of repressing ABCB7 on cisplatin cytotoxicity in group 3 MB and whether these effects were mediated by ferroptosis.In silicoandin vitroanalyses revealed specific enrichment of ABCB7 and GPX4, a critical regulator of ferroptosis, in group 3 MB cell lines and tumors. MiR-1253 overexpression (miR-1253OE) resulted in downregulation of both ABCB7 and GPX4, concurrently increasing mitochondrial iron overload, mitochondrial oxidative stress, and lipid peroxidation, leading to cell death and abrogation of medullosphere formation; repressing ABCB7 (si-ABC7 and ABCB7KO) recapitulated these effects and abrogated GPX4 expression. Fractionation studies confirmed the inhibitory impact of ABCB7 repression on GPX4 expression. Seahorse studies further revealed mitochondrial dysfunction with ABCB7 repression. Cisplatin, a chemotherapeutic agent used in group 3 MB treatment, induces cell death by DNA crosslinking; it also inhibits GPX4 expression and may trigger ferroptosis. In ABCB7-repressed group 3 cancer cells, cisplatin IC50was reduced 2-fold. Resultantly, cisplatin treatment augmented oxidative stress and lipid peroxidation, depleted glutathione stores, and culminated in a higher index of cell death via ferroptosis. In an orthotopic group 3 tumor model, ABCB7KOpotentiated cisplatin, prolonging survival and reducing tumor burden. Taken together, the current study illustrates how targeting iron transport can augment ferroptosis to potentiate cisplatin cytotoxicity in group 3 MB tumors..

Medienart:	Preprint

Erscheinungsjahr:	2023
Erschienen:	2023

Enthalten in:	bioRxiv.org - (2023) vom: 06. Juni Zur Gesamtaufnahme - year:2023

Sprache:	Englisch

Beteiligte Personen:

Kanchan, Ranjana K. [VerfasserIn] Perumal, Naveenkumar [VerfasserIn] Khan, Parvez [VerfasserIn] Doss, David [VerfasserIn] Gopalakrishnan, Prakadeeshwari [VerfasserIn] Venkata, Ramakanth Chirravuri [VerfasserIn] Thapa, Ishwor [VerfasserIn] Vengoji, Raghupathy [VerfasserIn] Kaushal, Jyoti B. [VerfasserIn] Siddiqui, Jawed A. [VerfasserIn] Nasser, Mohd Wasim [VerfasserIn] Batra, Surinder K. [VerfasserIn] Mahapatra, Sidharth [VerfasserIn]

Links:	Volltext [kostenfrei]

Themen:	570 Biology

doi:	10.1101/2022.01.24.477587

funding:
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PPN (Katalog-ID):	XBI03508250X