title: Inhibition of polo-like kinase 1 (Plk1) enhances the antineoplastic activity of metformin in prostate cancer.
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.
authors.affiliation: From the Departments of Biochemistry and.
authors.forename: Chen
authors.initials: C
authors.lastname: Shao
authors.affiliation: the Department of Dermatology, University of Wisconsin, Madison, Wisconsin 53706, and.
authors.forename: Nihal
authors.initials: N
authors.lastname: Ahmad
authors.affiliation: the Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202.
authors.forename: Kurt
authors.initials: K
authors.lastname: Hodges
authors.affiliation: Animal Sciences and.
authors.forename: Shihuan
authors.initials: S
authors.lastname: Kuang
authors.affiliation: the Purdue Center for Cancer Research, Purdue University, West Lafayette, Indiana 47907.
authors.forename: Tim
authors.initials: T
authors.lastname: Ratliff
authors.affiliation: From the Departments of Biochemistry and the Purdue Center for Cancer Research, Purdue University, West Lafayette, Indiana 47907, liu8@purdue.edu.
authors.forename: Xiaoqi
authors.initials: X
authors.lastname: Liu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002469:Cell Separation; D002470:Cell Survival; D018450:Disease Progression; D005434:Flow Cytometry; D006019:Glycolysis; D006801:Humans; D008297:Male; D008687:Metformin / Q000494:pharmacology; D051379:Mice; D008938:Mitosis; D009368:Neoplasm Transplantation; D017430:Prostate-Specific Antigen / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D011621:Pteridines / Q000494:pharmacology; D034622:RNA Interference; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D000097869:Polo-Like Kinase 1
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D008687:Metformin; D017430:Prostate-Specific Antigen; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011621:Pteridines; D016159:Tumor Suppressor Protein p53; D000097869:Polo-Like Kinase 1; C518477:BI 2536; C495901:TP53 protein, human
keywords: Cell Cycle; Metformin; Mitosis; Polo-like Kinase 1; Prostate Cancer; Serine/Threonine Protein Kinase; p53