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A small compound targeting TACC3 revealed its different spatiotemporal contributions for spindle assembly in cancer
1Department of Cell Biology, Cancer Institute, The Japanese Foundation for Cancer Research, Tokyo, Japan.
Abstract:
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.
Insights
A new compound, spindlactone (SPL), targets TACC3, inhibiting microtubule nucleation in ovarian cancer cells. This selective action disrupts spindle assembly, offering a novel therapeutic strategy for cancer treatment.
Area of Science:
- Cell Biology
- Molecular Oncology
- Cancer Therapeutics
Background:
- The mitotic spindle, crucial for cell division, is assembled by centrosomes and kinetochore microtubules.
- Transforming acidic coiled-coil (TACC) proteins are evolutionarily conserved regulators of spindle assembly.
- TACC3 is frequently overexpressed in human cancers, yet its precise role requires further investigation.
Purpose of the Study:
- To investigate the biological significance of TACC3 in cancer.
- To explore the therapeutic potential of targeting TACC3 using a novel compound, spindlactone (SPL).
- To elucidate the mechanism of action of TACC3 inhibition on microtubule dynamics and spindle formation.
Main Methods:
- Utilized spindlactone (SPL), a novel TACC3-targeting compound, in ovarian cancer cells.
- Assessed the effects of SPL on microtubule nucleation at centrosomes and kinetochores.
- Compared SPL effects with TACC3 and TOGp depletion.
- Evaluated SPL's efficacy in vivo tumor growth models.
Main Results:
- SPL selectively inhibited centrosome microtubule nucleation in ovarian cancer cells.
- Kinetochore microtubule assembly remained robust, leading to ectopic spindle poles and multipolar spindles.
- TACC3 inhibition partially suppressed kinetochore microtubule nucleation in a dose-dependent manner.
- SPL demonstrated significant in vivo tumor growth suppression without affecting normal cells.
Conclusions:
- TACC3 plays a critical role in microtubule nucleation, with distinct spatiotemporal contributions to centrosome and kinetochore microtubule assembly.
- Spindlactone (SPL) offers a targeted approach to cancer therapy by disrupting TACC3 function and spindle formation specifically in cancer cells.
- TACC3 represents a promising molecular target for developing novel chemotherapeutic strategies with improved efficacy and reduced toxicity compared to traditional microtubule toxins.
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