Journal of Biological Chemistry
Volume 290, Issue 4, 23 January 2015, Pages 2024-2033
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Signal Transduction
Inhibition of Polo-like Kinase 1 (Plk1) Enhances the Antineoplastic Activity of Metformin in Prostate Cancer*

https://doi.org/10.1074/jbc.M114.596817Get rights and content
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The widely used anti-diabetic drug metformin has been shown to exert strong antineoplastic actions in numerous tumor types, including prostate cancer (PCa). In this study, we show that BI2536, a specific Plk1 inhibitor, acted synergistically with metformin in inhibiting PCa cell proliferation. Furthermore, we also provide evidence that Plk1 inhibition makes PCa cells carrying WT p53 much more sensitive to low-dose metformin treatment. Mechanistically, we found that co-treatment with BI2536 and metformin induced p53-dependent apoptosis and further activated the p53/Redd-1 pathway. Moreover, we also show that BI2536 treatment inhibited metformin-induced glycolysis and glutamine anaplerosis, both of which are survival responses of cells against mitochondrial poisons. Finally, we confirmed the cell-based observations using both cultured cell-derived and patient-derived xenograft studies. Collectively, our findings support another promising therapeutic strategy by combining two well tolerated drugs against PCa proliferation and the progression of androgen-dependent PCa to the castration-resistant stage.Both inhibition of Plk1 and usage of metformin are reported to achieve strong antineoplastic functions in many cancers, including prostate cancer (PCa).

Results

Plk1 inhibitor BI2536 synergizes with metformin in controlling PCa cell growth.

Conclusion

Plk1 inhibition improves the antineoplastic function of metformin in PCa through both signaling and metabolic pathways.

Significance

The proposed combination therapy shows great potential for clinical trials.

Cell Cycle
Mitosis
p53
Prostate Cancer
Serine/Threonine Protein Kinase
Polo-like Kinase 1
Metformin

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*

This work was supported, in whole or in part, by National Institutes of Health Grants R01CA157429 (to X. L.) and R01AR059130 (to N. A.). This work was also supported by National Science Foundation Grant MCB-1049693 and American Cancer Society Grant RSG-13–073 (to X. L.) and by the China Scholarship Council (to C. S.). Xenograft data were acquired by a Purdue Center for Cancer Research facility supported by National Institutes of Health Grant P30 CA023168.