Reciprocal antagonism of PIN1-APC/C^CDH1 governs mitotic protein stability and cell cycle entry

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Induced oncoprotein degradation is a promising anti-cancer strategy.
• Anaphase-promoting complex (APC/C^CDH1) targets mitotic proteins for degradation, preventing cell-cycle entry.
• Regulation of APC/C^CDH1 activity and the role of peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1) in cancer remain unclear.

Purpose of the Study:

• To elucidate the regulatory mechanisms of APC/C^CDH1 and PIN1.
• To identify how these proteins govern mitotic protein stability and cell-cycle entry.
• To explore the therapeutic potential of combined PIN1 and cyclin-dependent protein kinases (CDKs) inhibition in triple-negative breast cancer.

Main Methods:

• Proteomic screening to identify protein interactions.
• Structural characterization of protein complexes.
• In vitro and in vivo assays to assess protein degradation and cell-cycle effects.

Main Results:

• A reciprocal antagonism between PIN1 and APC/C^CDH1 was identified, mediated by dual phosphorylation-dependent interactions.
• Combined PIN1 and CDK inhibition induces a positive feedback loop, activating APC/C^CDH1 and degrading PIN1 and other mitotic proteins.
• This leads to irreversible cell-cycle exit, triggers anti-tumor immunity, and demonstrates synergistic efficacy in triple-negative breast cancer models.

Conclusions:

• The interplay between PIN1 and APC/C^CDH1 is a fundamental mechanism controlling mitotic protein stability and cell-cycle progression.
• Combined inhibition of PIN1 and CDKs offers a novel therapeutic strategy with synergistic anti-cancer activity.
• This approach holds promise for treating aggressive cancers like triple-negative breast cancer by inducing permanent cell-cycle arrest and enhancing anti-tumor immunity.