Nek4 status differentially alters sensitivity to distinct microtubule poisons.
Microtubule poisons are widely used in cancer treatment, but the factors determining the relative efficacy of different drugs in this class remain obscure. In this study, we identified the NIMA kinase Nek4 in a genetic screen for mediators of the response to Taxol, a chemotherapeutic agent that stabilizes microtubules. After Taxol treatment, Nek4 promoted microtubule outgrowth, whereas Nek4 deficiency impaired G(2)-M arrest and decreased formation of mitotic-like asters. In contrast, Nek4 deficiency sensitized cells to vincristine, which destabilizes microtubules. Therefore, Nek4 deficiency may either antagonize or agonize the effects of microtubule poisons, depending on how they affect microtubule polymerization. Of note, Nek4 gene maps to a commonly deleted locus in non-small cell lung cancer. Thus, Nek4 deletion in this disease may rationalize the use of particular types of microtubule poisons for lung cancer therapy.
Doles
Jason
J
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Hemann
Michael T
MT
D000818:Animals; D015153:Blotting, Western; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D005434:Flow Cytometry / Q000379:methods; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008870:Microtubules / Q000378:metabolism*; D000072379:NIMA-Related Kinases; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology*; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D016019:Survival Analysis; D050257:Tubulin Modulators / Q000494:pharmacology; D014750:Vincristine / Q000494:pharmacology; D000099317:Hippo Kinases
D000072379:NIMA-Related Kinases; D017239:Paclitaxel; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D050257:Tubulin Modulators; D014750:Vincristine; C547589:NEK4 protein, human; C402650:SLK protein, mouse; D000099317:Hippo Kinases