Targeting Thioredoxin-1 by dimethyl fumarate induces ripoptosome-mediated cell death

Area of Science:

• Oncology
• Molecular Biology
• Immunology

Background:

• Constitutively active Nuclear Factor kappa B (NFκB) drives cancer cell survival, particularly in T-cell lymphomas and leukemias.
• NFκB upregulates antiapoptotic proteins, including inhibitors of apoptosis (IAPs) and FLICE-like inhibitory proteins (cFLIPs), which suppress programmed cell death pathways.

Purpose of the Study:

• To investigate the mechanism by which dimethyl fumarate (DMF) antagonizes NFκB signaling.
• To elucidate DMF's role in regulating cell death pathways, specifically apoptosis and necroptosis, in cancer cells.

Main Methods:

• Assessed DMF's effect on NFκB transcriptional activity by measuring Thioredoxin-1 (Trx1) suppression.
• Analyzed DMF-induced ripoptosome formation through the downregulation of IAPs and cFLIPs.
• Investigated DMF's impact on mitochondrial Smac release and IAP degradation in cancer cells.
• Examined ripoptosome formation and caspase-3 cleavage in T-cells from CTCL patients treated with DMF.

Main Results:

• DMF suppresses Thioredoxin-1 (Trx1), a key regulator of NFκB transcriptional activity.
• DMF-induced NFκB inhibition leads to ripoptosome formation via downregulation of IAPs and cFLIPs.
• DMF promotes mitochondrial Smac release, enhancing IAP degradation and tumor cell death.
• DMF treatment in CTCL patients resulted in ripoptosome formation and caspase-3 cleavage in T-cells.
• Malignant T-cells undergo both apoptosis and necroptosis upon DMF treatment, unlike resting T-cells.

Conclusions:

• DMF antagonizes NFκB by suppressing Trx1, leading to ripoptosome formation and enhanced cell death.
• Targeting NFκB via Trx1 suppression represents a novel therapeutic strategy for NFκB-dependent cancers.
• DMF selectively induces cell death in malignant or activated T-cells, highlighting its potential in T-cell malignancies.