Targeting ABCB6 induces ferroptosis in osteosarcoma cells via HIF1A/GPX4 pathway

Area of Science:

• Oncology
• Molecular Biology
• Cell Death Mechanisms

Background:

• Osteosarcoma (OS) exhibits poor prognosis due to metastasis and chemoresistance, necessitating new therapeutic targets.
• Ferroptosis, an iron-dependent cell death, presents a potential strategy to overcome treatment resistance in tumors.
• ATP-binding cassette subfamily B member 6 (ABCB6) is implicated in various cancers, but its role in OS is unknown.

Purpose of the Study:

• To investigate the expression, prognostic significance, and biological functions of ABCB6 in osteosarcoma.
• To elucidate the molecular mechanism by which ABCB6 influences ferroptosis in OS cells.
• To provide a basis for developing ABCB6-targeted therapies for osteosarcoma.

Main Methods:

• Utilized human OS cell lines and bone marrow mesenchymal stem cells (BMSCs).
• Employed lentivirus-mediated RNA interference for ABCB6 knockdown and rescue experiments with hypoxia-inducible factor 1-alpha (HIF1A) overexpression.
• Assessed cell proliferation, migration, apoptosis, and ferroptosis markers; performed transcriptome sequencing, chromatin immunoprecipitation (ChIP), and dual-luciferase reporter assays.

Main Results:

• ABCB6 expression was elevated in OS cells and associated with worse survival in patients.
• ABCB6 knockdown suppressed proliferation, migration, and induced apoptosis and ferroptosis in OS cells.
• The study identified a novel axis: ABCB6 regulates Fe2+ levels, impacting HIF1A stability, which in turn controls GPX4 transcription, thereby governing ferroptosis.

Conclusions:

• ABCB6 plays an oncogenic role in OS and serves as a prognostic biomarker.
• The identified 'ABCB6/Fe2+/HIF1A/GPX4' axis is crucial for regulating ferroptosis in OS.
• Targeting this axis offers a promising therapeutic strategy for osteosarcoma treatment.