Inhibition of Polo-like Kinase 1 (Plk1) Enhances the Antineoplastic Activity of Metformin in Prostate Cancer |
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Authors: | Chen Shao Nihal Ahmad Kurt Hodges Shihuan Kuang Tim Ratliff Xiaoqi Liu |
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Institution: | From the Departments of ‡Biochemistry and ;‖Animal Sciences and ;the **Purdue Center for Cancer Research, Purdue University, West Lafayette, Indiana 47907.;the §Department of Dermatology, University of Wisconsin, Madison, Wisconsin 53706, and ;the ¶Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202 |
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Abstract: | 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. |
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Keywords: | Cell Cycle Mitosis p53 Prostate Cancer Serine/Threonine Protein Kinase Polo-like Kinase 1 Metformin |
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