Nakiterpiosin targets tubulin and triggers mitotic catastrophe in human cancer cells.
Agents that interfere with mitotic progression by perturbing microtubule dynamics are commonly used for cancer chemotherapy. Here, we identify nakiterpiosin as a novel antimitotic drug that targets microtubules. Nakiterpiosin induces mitotic arrest and triggers mitotic catastrophe in human cancer cells by impairing bipolar spindle assembly. At higher concentration, it alters the interphase microtubule network and suppresses microtubule dynamics. In the presence of nakiterpiosin, microtubules are no longer arranged in a centrosomal array and centrosome-mediated microtubule regrowth after cold depolymerization is inhibited. However, centrosome organization, the ultrastructure of Golgi stacks, and protein secretion are not affected, suggesting that the drug has minimal toxicity toward other cellular functions. Nakiterpiosin interacts directly with tubulin, inhibits microtubule polymerization in vitro, and decreases polymer mass in cells. Furthermore, it enhances tubulin acetylation and reduces viability of paclitaxel-resistant cancer cells. In conclusion, nakiterpiosin exerts antiproliferative activity by perturbing microtubule dynamics during mitosis that activates the spindle assembly checkpoint and triggers cell death. These findings suggest the potential use of nakiterpiosin as a chemotherapeutic agent.
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Jen-Hsuan
JH
Wei
Joachim
J
Seemann
D000107:Acetylation / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018385:Centrosome / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D002877:Chromosomes, Human / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006056:Golgi Apparatus / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D006718:Homosteroids / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007399:Interphase / Q000187:drug effects; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D008938:Mitosis / Q000187:drug effects*; D015739:Nocodazole / Q000737:chemistry / Q000494:pharmacology; D017239:Paclitaxel / Q000737:chemistry / Q000494:pharmacology; D058105:Polymerization / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D008941:Spindle Apparatus / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D014404:Tubulin / Q000378:metabolism*
C405804:EB1 microtubule binding proteins; D006718:Homosteroids; D008869:Microtubule-Associated Proteins; D014404:Tubulin; C539406:nakiterpiosin; D017239:Paclitaxel; D015739:Nocodazole