Restoration of chemosensitivity to drug resistant breast cancer cells through peptide activation of Anaphase Promoting Complex

Abstract The primary care of cancer patients involves improving their outcomes, resulting in longer remission periods and, in some cases, cures. However, many cancers eventually return to a state that is too resistant to therapy. 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 activation of the Anaphase Promoting Complex (APC) resensitized recurrent MDR malignancies in vitro, independent of cancer type, chemotherapy exposure, or species. Specifically, the indirect APC chemical activator, M2I-1, resensitized MDR canine lymphoma cells and human breast cancer cells to first-line therapy. In this study, we applied small peptides that were discovered via a yeast 2-hybrid screen for peptides that interact with the Apc10 APC subunit as direct activators of the APC. The tested peptides indeed increased APC activity, as indicated by reduced APC protein substrate levels, increased (activating) phosphorylation of APC1S355, and increased E3 ligase activity, as determined via in vitro ubiquitination assays. One peptide significantly restored chemosensitivity to the MDA-MB-231 breast cancer cell line in vitro and in an in vivo mouse model. The peptides induced mitotic catastrophe, increased DNA damage, and activated apoptotic pathways. Taken together, our results demonstrate that direct activation of the APC via a small APC-activating peptide has anticancer effects both in vitro and in vivo in MDR breast cancer cells, suggesting the potential for targeted treatment to improve patient outcomes.