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A synthetic lethal interaction between APC/C and topoisomerase poisons uncovered by proteomic screens

Manuel Eguren1, Mónica Álvarez-Fernández1, Fernando García2

  • 1Cell Division and Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.

Cell Reports
|February 11, 2014
PubMed

Insights

The Anaphase-promoting complex/cyclosome (APC/C) cofactor Cdh1 targets proteins to maintain genomic stability. Loss of Cdh1 increases sensitivity to Topoisomerase 2α poisons, suggesting new cancer treatment strategies.

Area of Science:

  • Cell Biology
  • Genetics
  • Molecular Biology

Background:

  • The Anaphase-promoting complex/cyclosome (APC/C) cofactor Cdh1 regulates cell proliferation by degrading cell-cycle proteins.
  • Cdh1 deficiency leads to chromosome instability, a characteristic of cancer.

Purpose of the Study:

  • To identify novel Cdh1 targets involved in maintaining genomic stability.
  • To explore the therapeutic implications of APC/C-Cdh1 function in cancer.

Main Methods:

  • Proteomic analysis in Cdh1-null cells and mouse tissues.
  • Ubiquitination and degradation assays.
  • Sensitivity assays for Eg5 and Topoisomerase 2α inhibitors.

Main Results:

  • Kinesin Eg5 and topoisomerase 2α (Top2α) were identified as novel Cdh1 targets.
  • Cdh1-null cells showed resistance to Eg5 inhibitors but increased sensitivity to Top2α poisons.
  • Inhibition of APC/C in cancer cells enhanced sensitivity to Top2α poisons.

Conclusions:

  • Cdh1 directly regulates Eg5 and Top2α stability, crucial for genomic integrity.
  • Targeting APC/C-Cdh1 interactions with Top2α poisons presents a potential synthetic lethal strategy for cancer therapy.

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