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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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier Inc. All rights reserved.)

Background: It is controversial if urothelial carcinoma of the bladder with squamous and/or glandular differentiation is a more aggressive neoplasm than conventional urothelial carcinoma., Design: A total of 165 transurethral resections of the bladder were reviewed. A group with squamous and/or glandular differentiation was compared to a group without this finding. The chi-square test was used to assess the association of the groups with stage (TNM, 1997)., Results: Of the total of 165 transurethral resections of the bladder, 153 (92.72%) were conventional urothelial carcinomas and 12 (7.27%) showed squamous and/or glandular differentiation. The distribution according to stage was 84 (54.9%), 35 (22.9%) and 34 (22.2%) for the group without differentiation and 0 (0%), 3 (25%) and 9 (75%) for the group with squamous and/or glandular differentiation, respectively for stages pTa, pT1 and pT2. Tumors with squamous and/or glandular differentiation showed a significant statistical correlation to higher stage at clinical presentation (p < 0.0001). There was no significant statistical relation according to age (p = 0.8433), sex (p = 0.5672) or race (p = 0.3137)., Conclusions: The results suggest that urothelial bladder carcinomas with squamous and/or glandular differentiation are more aggressive neoplasms. There was a significant statistical correlation between tumors with this differentiation and higher stage at clinical presentation.