Bladder cancer (BC) is a common urological malignancy that still lacks an effective treatment. Doxorubicin (Dox) has been widely used in the treatment of various cancers, including BC. However, chemoresistance often hampers the clinical application of Dox, therefore, it is necessary to develop effective strategies to improve its efficacy. By using high-throughput screening, we identified OSU-T315, an integrin-linked kinase (ILK) inhibitor, that can augment the cytotoxicity of Dox against BC cells. We found that OSU-T315 and Dox synergistically induce apoptosis of BC cells via mitochondrial pathway in a caspase-dependent. Mechanically, it was found that OSU-T315 and Dox synergistically induced activation of Bax which is critical for the induction of apoptosis. Moreover, it was also found that the downregulation of BCL-2 and MCL-1 is essential for the activation of BAX induced by OSU-T315 and Dox. OSU-T315 was found to downregulate MCL-1 via the GSK-3β/FBXW7 axis in BC cells. Our findings suggest that combined treatment with OSU-T315 and Dox may be a promising strategy to treat BC.
Keywords: Mcl-1; OSU-T315; apoptosis; bladder cancer; doxorubicin.
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