Importin α/β inhibition as a strategy to modulate cancer drug resistance and XIAP nuclear translocation

Shuttling from the cytoplasm to the nucleus is a regulated cellular process which involves the recognition of nuclear localization signal-containing proteins by importins. Nuclear-cytoplasmic protein transport is found aberrant in cancer, which impacts subcellular localization of proteins that modulate drug responses and cell growth. We have previously demonstrated that the classically cytoplasmic antiapoptotic XIAP protein is associated with breast cancer chemoresistance and poorer clinical outcomes, when mis localized in the nucleus. Nevertheless, little is known about the mechanisms of XIAP nuclear translocation. In this study, we compared importin expression and response to importin inhibitors in cancer cellular models with distinct drug sensitivity phenotypes and subcellular localization of XIAP. Remarkably, importins α1, α5 and β1 were found differentially expressed among drug sensitive and resistant cell lines, as well as primary breast tumors compared to normal tissues. Interestingly, nuclear XIAP-expressing cancer cells exhibiting resistance to both docetaxel and doxorubicin have shown pronounced sensitivity to importin inhibition. Pharmacological intervention of nuclear transport revealed that XIAP can shuttle from the cytoplasm to the nucleus dependently on the importins α/β1 classical pathway. Last, we have shown that INI-43-mediated inhibition of importins α/β1 potentiates the cytotoxic effects of chemotherapy in drug refractory cells. These findings indicate that targeting protein nuclear import via importins α and β1 might be of potential clinical benefit for drug resistance tumors, particularly when combined with conventional chemotherapy.