Dual Inhibition of γ-Tubulin and Plk1 Induces Mitotic Cell Death
Haruna Ebisu1, Kana Shintani1, Takumi Chinen1,2,3
1Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Japan.
Abstract:
α/β-Tubulin inhibitors that alter microtubule (MT) dynamics are commonly used in cancer therapy, however, these inhibitors also cause severe side effects such as peripheral neuropathy. γ-Tubulin is a possible target as antitumor drugs with low side effects, but the antitumor effect of γ-tubulin inhibitors has not been reported yet. In this study, we verified the antitumor activity of gatastatin, a γ-tubulin specific inhibitor. The cytotoxicity of gatastatin was relatively weak compared with that of the conventional MT inhibitors, paclitaxel and vinblastine. To improve the cytotoxicity, we screened the chemicals that improve the effects of gatastatin and found that BI 2536, a Plk1 inhibitor, greatly increases the cytotoxicity of gatastatin. Co-treatment with gatastatin and BI 2536 arrested cell cycle progression at mitosis with abnormal spindles. Moreover, mitotic cell death induced by the combined treatment was suppressed by the Mps1 inhibitor, reversine. These findings suggest that co-treatment with Plk1 and γ-tubulin inhibitors causes spindle assembly checkpoint-dependent mitotic cell death by impairing centrosome functions. These results raise the possibility of Plk1 and γ-tubulin inhibitor co-treatment as a novel cancer chemotherapy.
Insights
Novel cancer therapy combines γ-tubulin and Plk1 inhibitors to induce mitotic cell death. This approach targets cancer cells specifically, potentially reducing side effects associated with traditional microtubule inhibitors.
Area of Science:
- Oncology
- Cell Biology
- Pharmacology
Background:
- Microtubule (MT)-targeting drugs are standard cancer therapies but cause severe side effects like peripheral neuropathy.
- γ-Tubulin is a potential anticancer target due to its role in cell division and the possibility of fewer side effects.
- The antitumor effects of γ-tubulin inhibitors have not been previously established.
Purpose of the Study:
- To investigate the antitumor activity of gatastatin, a specific inhibitor of γ-tubulin.
- To identify compounds that enhance the efficacy of gatastatin.
- To elucidate the mechanism of action for combined γ-tubulin and Plk1 inhibition in cancer treatment.
Main Methods:
- Cytotoxicity assays comparing gatastatin with conventional MT inhibitors (paclitaxel, vinblastine).
- Screening for chemicals that potentiate gatastatin's effects, identifying BI 2536 (Plk1 inhibitor).
- Cell cycle analysis and assessment of mitotic cell death in co-treated cells, with suppression studies using reversine (Mps1 inhibitor).
Main Results:
- Gatastatin exhibited weaker cytotoxicity than paclitaxel and vinblastine.
- BI 2536 significantly enhanced the cytotoxicity of gatastatin.
- Co-treatment with gatastatin and BI 2536 induced mitotic arrest with abnormal spindles and mitotic cell death.
- This cell death was dependent on the spindle assembly checkpoint and involved impaired centrosome function.
Conclusions:
- Combined inhibition of Plk1 and γ-tubulin induces spindle assembly checkpoint-dependent mitotic cell death.
- This combination therapy targets centrosome function, offering a novel strategy for cancer treatment.
- Plk1 and γ-tubulin inhibitor co-treatment presents a promising avenue for developing new cancer chemotherapies with potentially reduced side effects.
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