ABSTRACT
A limited number of studies have indicated an association of the mitotic kinase polo-like kinase 1 (PLK1) and cellular metabolism. Here, employing an inducible RNA interference approach in A375 melanoma cells coupled with a PCR array and multiple validation approaches, we demonstrated that PLK1 alters a number of genes associated with cellular metabolism. PLK1 knockdown resulted in a significant downregulation of IDH1, PDP2 and PCK1 and upregulation of FBP1. Ingenuity Pathway Analysis (IPA) identified that 1) glycolysis and the pentose phosphate pathway are major canonical pathways associated with PLK1, and 2) PLK1 inhibition-modulated genes were largely associated with cellular proliferation, with FBP1 being the key modulator. Further, BI 6727-mediated inhibition of PLK1 caused a decrease in PCK1 and increase in FBP1 in A375 melanoma cell implanted xenografts in vivo. Furthermore, an inverse correlation between PLK1 and FBP1 was found in melanoma cells, with FBP1 expression significantly downregulated in a panel of melanoma cells. In addition, BI 6727 treatment resulted in an upregulation in FBP1 in A375, Hs294T and G361 melanoma cells. Overall, our study suggests that PLK1 may be an important regulator of metabolism maintenance in melanoma cells.
Subject(s)
Cell Cycle Proteins/metabolism , Energy Metabolism , Gene Knockdown Techniques , Melanoma/enzymology , Protein Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins/metabolism , RNA Interference , Skin Neoplasms/enzymology , Animals , Cell Cycle Proteins/genetics , Cell Line, Tumor , Cell Proliferation , Down-Regulation , Fructose-Bisphosphatase/genetics , Fructose-Bisphosphatase/metabolism , Gene Expression Regulation, Enzymologic , Gene Expression Regulation, Neoplastic , Gene Regulatory Networks , HEK293 Cells , Humans , Intracellular Signaling Peptides and Proteins/genetics , Intracellular Signaling Peptides and Proteins/metabolism , Isocitrate Dehydrogenase/genetics , Isocitrate Dehydrogenase/metabolism , Melanoma/genetics , Melanoma/pathology , Mice , Phosphoenolpyruvate Carboxykinase (GTP)/genetics , Phosphoenolpyruvate Carboxykinase (GTP)/metabolism , Protein Serine-Threonine Kinases/genetics , Proto-Oncogene Proteins/genetics , Pyruvate Dehydrogenase (Lipoamide)-Phosphatase/genetics , Pyruvate Dehydrogenase (Lipoamide)-Phosphatase/metabolism , Signal Transduction , Skin Neoplasms/genetics , Skin Neoplasms/pathology , Transfection , Tumor Burden , Polo-Like Kinase 1ABSTRACT
Polo-like kinase 1 (Plk1) overexpression has been shown to occur in a wide range of tumors, prompting research and development of Plk1 inhibitors as a means of cancer treatment. This review discusses recent advances in the development of Plk1 inhibitors for cancer management. Plk1 inhibition has been shown to cause mitotic block and apoptosis of cells with higher mitotic index and therefore higher Plk1 expression. The potential of Plk1 inhibitors as cancer therapeutics has been widely investigated. However, a complete understanding of Plk1 biology/mechanism is yet to be fully achieved. Resistance to certain chemotherapeutic drugs has been linked to Plk1 overexpression, and Plk1-mediated mitotic events such as microtubule rearrangement have been found to reduce the efficacy of chemotherapeutic agents. The Plk1 inhibitor volasertib has shown considerable promise in clinical studies, having reached phase III trials. However, preclinical success with Plk1 inhibitors has not translated well into clinical success. In our view, combined therapies targeting other relevant pathways together with Plk1 may be vital to combat issues observed with monotherapy, especially resistance. In addition, research should also be directed toward understanding the mechanisms of Plk1 and designing additional next generations of specific, potent Plk1 inhibitors to target cancer. Mol Cancer Ther; 15(7); 1427-35. ©2016 AACR.