The Use of APC/C Antagonists to Promote Mitotic Catastrophe in Cancer Cells

Area of Science:

• Cell Biology
• Molecular Biology
• Cancer Research

Background:

• The Anaphase-Promoting Complex/Cyclosome (APC/C) is a crucial E3 ubiquitin ligase regulating mitosis progression.
• APC/C is the effector of the Spindle Assembly Checkpoint (SAC), ensuring accurate chromosome segregation during cell division.
• Dysfunctional SAC signaling leads to genome instability, aneuploidy, premature aging, and cancer.

Purpose of the Study:

• To investigate the potential of small molecules as antagonists of APC/C activation by Cdc20.
• To evaluate the efficacy of these molecules in inducing mitotic catastrophe and suppressing cancer cell proliferation.

Main Methods:

• Utilized commercially available (Apcin, proTAME) and novel small molecules targeting APC/C-Cdc20 interaction.
• Tested these molecules alone and in combination on various cancer cell lines (breast, cervical, ovarian).
• Assessed effects on cell expansion in 2D cultures and 3D spheroids.

Main Results:

• Small molecules effectively interfered with APC/C activation by Cdc20.
• Inhibition of APC/C-Cdc20 interaction led to delayed mitotic exit and induced mitotic catastrophe.
• Demonstrated suppression of cancer cell expansion in both 2D and 3D models.

Conclusions:

• Targeting APC/C activation by Cdc20 with small molecules is a viable strategy to induce cancer cell death.
• This approach holds potential for therapeutic intervention in cancers associated with SAC dysregulation.
• The developed molecules effectively promote mitotic catastrophe and inhibit cancer cell growth.