Taxol affects nuclear lamina and pore complex organization and inhibits import of karyophilic proteins into the cell nucleus

Treatment of human carcinoma cells with Taxol induces focal unraveling of t he nuclear lamina and extensive clustering or ectopic localization of the n uclear pore complexes. These striking aberrations develop when the cells ar e transferred to drug-free medium and are allowed to complete mitosis, As c ould be confirmed by terminal deoxynucleotidyl transferase-mediated nick en d labeling assays, 4,6-diamidino-2-phenylindole staining, 5-bromo-2-deoxyur idine incorporation, and examination of the nuclear lamins by Western blott ing, the malformation of the nuclear envelope is not a consequence of apopt osis or G(1), arrest. In fact, Taxol-treated cells possessing a defective n uclear envelope remain alive and replication competent for at least 24 h, u ndergoing programmed death 72 h after removal of the drug. While still in t he nonapoptotic state, these cells Lose the ability to import karyophilic p roteins into the nucleus. Diminished nucleocytoplasmic transport through th e nuclear pore complex can be readily demonstrated by in vitro assays invol ving digitonin-permeabilized cells or irt vivo monitoring of nuclear factor -kappa B translocation upon stimulation with tumor necrosis factor-alpha. T hese observations reveal novel cellular targets of antimicrotubule drugs an d may pave the way for improved schemes of anticancer treatment.