A small compound targeting TACC3 revealed its different spatiotemporal contributions for spindle assembly in cancer cells.
The mitotic spindle is assembled by the coordinated action of centrosomes and kinetochore microtubules. An evolutionally conserved protein family, transforming acidic coiled-coil (TACC), has been shown to be involved in this process. In humans, TACC3 is aberrantly expressed in a variety of human cancers, but its biological significance remains to be elucidated. Here, using a novel compound targeting TACC3, spindlactone (SPL), we show that the perturbation of TACC3 selectively inhibited the nucleation of centrosome microtubules in ovarian cancer cells. In contrast to centrosome microtubules, the kinetochore microtubules were robustly assembled, forming ectopic spindle poles that resulted in multipolar spindles. Interestingly, the extensive inhibition of TACC3 partially suppressed the nucleation of kinetochore microtubules. These dose-dependent effects of SPL were consistent with the results observed by the depletion of TACC3 and its binding partner, colonic and hepatic tumor overexpressed gene protein (TOGp). Although these proteins both have roles in the assembly of centrosome and kinetochore microtubules, their contributions were spatiotemporally different. Notably, SPL did not affect spindle assembly in normal cells. Furthermore, the oral administration of SPL significantly suppressed tumor growth in vivo. The unique mechanism of action of SPL not only enables it to be used as a tool to dissect the molecular basis of spindle assembly but also to provide a rationale for the use of TACC3 as a molecular target for cancer treatment. This rationale offers an opportunity to develop new strategies for cancer chemotherapy that overcome the limitations of microtubule toxins and expand their scope and clinical efficacy.
Department of Cell Biology, Cancer Institute, The Japanese Foundation for Cancer Research, Tokyo, Japan.
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R
Yao
Chemical Biology Core Facility, RIKEN Advanced Science Institute, Saitama, Japan.
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Y
Kondoh
Department of Cell Biology, Cancer Institute, The Japanese Foundation for Cancer Research, Tokyo, Japan.
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Y
Natsume
Department of Cell Biology, Cancer Institute, The Japanese Foundation for Cancer Research, Tokyo, Japan.
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Yamanaka
1] Department of Cell Biology, Cancer Institute, The Japanese Foundation for Cancer Research, Tokyo, Japan [2] Team for the Advanced Development and Evaluation of Human Disease Models, Bioresource Center, RIKEN, Tsukuba, Japan.
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M
Inoue
Team for the Advanced Development and Evaluation of Human Disease Models, Bioresource Center, RIKEN, Tsukuba, Japan.
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H
Toki
Chemical Biology Core Facility, RIKEN Advanced Science Institute, Saitama, Japan.
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R
Takagi
Chemical Biology Core Facility, RIKEN Advanced Science Institute, Saitama, Japan.
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Shimizu
Division of Molecular Pharmacology, Cancer Chemotherapy Center, The Japanese Foundation for Cancer Research, Tokyo, Japan.
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Yamori
Chemical Biology Core Facility, RIKEN Advanced Science Institute, Saitama, Japan.
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H
Osada
1] Department of Cell Biology, Cancer Institute, The Japanese Foundation for Cancer Research, Tokyo, Japan [2] Team for the Advanced Development and Evaluation of Human Disease Models, Bioresource Center, RIKEN, Tsukuba, Japan.
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Noda
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018385:Centrosome / Q000378:metabolism; D003374:Coumarins / Q000494:pharmacology*; D064593:Heterografts; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008870:Microtubules / Q000378:metabolism; D008941:Spindle Apparatus / Q000378:metabolism*; D059008:Time-Lapse Imaging; D047368:Tumor Burden / Q000187:drug effects
D000970:Antineoplastic Agents; D003374:Coumarins; D008869:Microtubule-Associated Proteins; C120551:TACC3 protein, human; C000592355:spindlactone A; C000592356:spindlactone B