title: Comparison of cancer cell survival triggered by microtubule damage after turning Dyrk1B kinase on and off.
abstract: 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.
authors.affiliation: School of Chemistry and Chemical Engineering, Shandong University , Jinan, China 250100.
authors.forename: Liwen
authors.initials: L
authors.lastname: Li
authors.forename: Yin
authors.initials: Y
authors.lastname: Liu
authors.forename: Qiu
authors.initials: Q
authors.lastname: Zhang
authors.forename: Hongyu
authors.initials: H
authors.lastname: Zhou
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Bing
authors.initials: B
authors.lastname: Yan
mesh_terms: D015153:Blotting, Western; D018929:Cell Culture Techniques; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D008856:Microscopy, Fluorescence; D008870:Microtubules / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D050257:Tubulin Modulators / Q000494:pharmacology*; D000097603:Dyrk Kinases
chemical_list: D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D050257:Tubulin Modulators; D000097603:Dyrk Kinases