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.
ASJC Scopus subject areas
- Molecular Medicine