Selective HSP90β inhibition results in TNF and TRAIL mediated HIF1α degradation

Area of Science:

• Cellular Biology
• Molecular Biology
• Immunology

Background:

• Tumor Necrosis Factor Receptor 1 (TNF-R1) signaling triggers diverse cellular responses, including inflammation, proliferation, and cell death.
• Pro-survival signals originate from membrane-bound TNF-R1 complexes (complex I), while apoptosis induction requires internalized complexes (complex II) for DISC formation.
• Internalized TNF-R1 complexes mature into lysosomes, activating Cathepsin D (CtsD), which cleaves HSP90, amplifying cell death.

Purpose of the Study:

• To investigate the role of HSP90β degradation in TNF-R1 and TRAIL-mediated extrinsic cell death.
• To identify downstream targets of combined death ligand stimulation and HSP90β inhibition.
• To explore the therapeutic potential of targeting HSP90 isoforms in conjunction with death ligands.

Main Methods:

• Western blotting to assess protein degradation (HSP90β, HIF1α).
• Cell viability assays using TNF or TRAIL with HSP90 inhibitors (KUNB105, HSP90α selective inhibitor).
• Analysis of downstream signaling pathways involved in apoptosis.

Main Results:

• Extrinsic cell death activation via TNF or TRAIL leads to HSP90β degradation.
• Co-treatment with TNF or TRAIL and the HSP90β inhibitor KUNB105 significantly enhanced apoptosis compared to HSP90α inhibition.
• HIF1α was identified as a downstream target degraded upon combined death ligand and HSP90β inhibition.

Conclusions:

• Selective inhibition of HSP90β, in combination with death ligand stimulation, promotes apoptosis.
• Targeting HSP90 isoforms alongside death receptor activation presents a promising strategy for treating inflammatory diseases and cancer.