Comparison of cancer cell survival triggered by microtubule damage after turning Dyrk1B kinase on and off.

Using a tubulin polymerization inhibitor and a tubulin polymerization/Dyrk1B dual inhibitor, we intentionally allowed or blocked the Dyrk1B-coordinated cell survival process in response to microtubule damage. By examining the resulting differential effects on cell function and phenotype, we have elucidated key molecular interactions involved in the Dyrk1B-coordinated cell survival process as well as the associated overall cellular impact. Dyrk1B activation that is induced by microtubule damage triggers microtubule stabilization and promotes the mitochondrial translocation of p21(Cip1/waf1) (referred to as p21 hereafter) to suppress apoptosis. These coordinated survival events rapidly repair microtubules, relieve cell G2/M arrest for 42% of the cells, suppress apoptosis for 27% of the cells, and increase cell viability by 10-fold. That is, the dual inhibitor is 10 times more potent in the inhibition of cancer cell viability. This approach affords a novel drug discovery strategy by targeting both the therapeutic targets and the associated cell survival pathway using a single therapeutic agent.