Restoration of chemosensitivity to drug resistant breast cancer cells through peptide activation of the anaphase promoting complex.

Abstract

UNLABELLED: Clinical cancer management goals involve improving patient outcomes, extending remission periods and, in some cases, providing a cure. However, many cancers eventually develop a treatment-resistant form, even decades after initial responses. Once cancers become multidrug resistant (MDR) and aggressive, palliative care or more toxic therapies are the remaining options for this growing population of cancer survivors. New approaches to resensitize MDR malignancies to nontoxic therapies are critically important to improve patient outcomes. Previously, we reported that indirect chemical activation of the Anaphase Promoting Complex (APC) resensitized recurrent MDR malignancies in vitro to chemotherapy, independent of cancer type, chemotherapy exposure, or species. In this study, we identified small peptides via a yeast 2-hybrid screen that interacted with the yeast Apc10 APC subunit, providing direct APC activation. Two of the tested yeast-derived peptides increased APC activity in human cells, as indicated by reduced APC protein substrate levels, increased (activating) phosphorylation of APC1S355, and increased E3 ligase activity, as determined utilizing in vitro ubiquitination assays. By enhancing APC activity, the peptides induced mitotic catastrophe, increased DNA damage, and activated apoptotic pathways, thereby elevating sensitivity to subsequent doxorubicin treatment. Remarkedly, one peptide significantly restored chemosensitivity in the MDA-MB-231 breast cancer cell line in an in vivo mouse xenograft model. Taken together, our results demonstrate that direct activation of the APC via small APC-activating peptides has anticancer effects both in vitro and in vivo in MDR breast cancer cells, suggesting the potential for targeted treatment to improve patient outcomes, including those with treatment resistance. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at https://doi.org/10.1038/s41598-026-61328-6.

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