AP-1 inhibitor induces ferroptosis via the PI3K/AKT pathway in multiple myeloma cells

Area of Science:

• Oncology
• Molecular Biology
• Cell Death Research

Background:

• Multiple myeloma (MM) is an incurable plasma cell malignancy.
• T-5224, an AP-1 inhibitor, shows anti-MM activity by inhibiting proliferation and inducing apoptosis.
• The precise mechanisms of T-5224-induced MM cell death, particularly ferroptosis, remain unexplored.

Purpose of the Study:

• To investigate the role of ferroptosis in T-5224-mediated killing of MM cells.
• To elucidate the molecular pathways involved in T-5224-induced ferroptosis.
• To explore the potential synergistic effects of T-5224 with bortezomib for MM treatment.

Main Methods:

• In vitro and in vivo studies using MM cell lines and xenograft models.
• Treatment with T-5224 and ferroptosis inhibitor (Fer-1).
• Assessment of cell death, protein levels (GPX4, SLC7A11), and signaling pathway phosphorylation (PI3K/AKT).
• Evaluation of combination therapy with bortezomib (BTZ).

Main Results:

• T-5224 demonstrated antimyeloma properties in vitro and in vivo.
• T-5224-induced MM cell death was significantly reversed by Fer-1.
• T-5224 decreased GPX4 and SLC7A11 protein levels and inhibited PI3K/AKT phosphorylation.
• T-5224 induces MM cell ferroptosis via the PI3K/AKT pathway.

Conclusions:

• T-5224 induces multiple myeloma cell death through ferroptosis, mediated by the PI3K/AKT pathway.
• This study provides a novel mechanistic insight into T-5224's antimyeloma effects.
• T-5224 represents a potential therapeutic agent for MM, possibly in combination with existing treatments like BTZ.