Synuclein γ compromises spindle assembly checkpoint and renders resistance to antimicrotubule drugs

Area of Science:

• Oncology
• Molecular Biology
• Cell Biology

Background:

• Defects in the spindle assembly checkpoint (SAC) are linked to chromosomal instability in human cancers.
• Antimicrotubule drug (AMD) resistance often arises from acquired SAC inactivation.
• Synuclein gamma (SNCG) is a breast cancer-specific gene highly expressed in malignant cells.

Purpose of the Study:

• To investigate the role of SNCG in mediating resistance to AMD-induced apoptosis.
• To elucidate the molecular mechanism by which SNCG affects SAC function.
• To correlate SNCG expression with chemotherapy response in breast cancer patients.

Main Methods:

• In vitro assays using breast cancer cells and cancer xenografts.
• Biochemical analysis of SNCG-BubR1 interaction, including binding site mapping (SNCG C-terminal to BubR1 N-terminal TPR motif).
• Assessment of SAC protein interactions (BubR1, Cdc20) and function.
• Analysis of patient tumor samples from a neoadjuvant clinical trial.

Main Results:

• SNCG expression is sufficient to induce resistance to AMD-induced apoptosis in breast cancer models.
• SNCG directly binds to BubR1 and inhibits its kinase activity.
• The SNCG-BubR1 interaction alters BubR1 structure, weakens its binding to Cdc20, and compromises SAC function.
• SNCG-positive tumors in patients showed resistance to chemotherapy-induced apoptosis.

Conclusions:

• SNCG promotes resistance to antimicrotubule drugs by inhibiting BubR1 activity and attenuating spindle assembly checkpoint function.
• SNCG represents a mechanism for chemotherapy resistance in breast cancer.
• Targeting the SNCG-BubR1 interaction could be a therapeutic strategy for overcoming AMD resistance.