Function of Polo-like kinase 1 and its research progress in tumor therapy / 国际外科学杂志

Protein kinases are key regulators of cellular function and constitute one of the largest and participate in orch estrating the vast majority of cellular activities, forming a criss-cross regulatong network. Kinases, which play a key role in regulating the activity of cellular proteins, are prime targets for anticancer drugs because their abnormal forms can promote the proliferation of tumor cells. Polo-like kinase-1 (Plk-1) is a member of the polo-like family of serine/threonine (Ser/Thr) kinases, which is involved in many aspects of the mitotic process that regulates cell proliferation, which is one of the key kinases of cell mitosis, whose overexpression is closely related to the occurrence and development of many human cancers. Drug development targeting Plk-1 may be one of the promising directions for the treatment of cancer. This review will summarize the structural features of Plk-1 and the cellular processes involved, as well as the rationale for anti-tumor therapy against Plk-1, the latest progress in inhibitor development and the latest strategies.

Mining Polo-Box domain of Polo-like kinase 1 as a new therapeutic target for cancer / 生物工程学报

Polo-like kinase 1 (Plk1) is widely regarded as one of the most promising targets for cancer therapy due to its essential role in cell division and tumor cell survival. At present, most Plk1 inhibitors have been developed based on kinase domain, some of which are in clinical trial. However, inhibitors targeting kinase domain face off-target effect and drug resistance owing to the conserved nature and the frequent mutations in the ATP-binding pocket. In addition to a highly conserved kinase domain, Plk1 also contains a unique Polo-Box domain (PBD), which is essential for Plk1's subcellular localization and mitotic functions. Inhibitors targeting Plk1 PBD show stronger selectivity and less drug resistance for cancer therapy. Therefore, Plk1 PBD is an attractive target for the development of anti-cancer agents. In this review, we will summarize the up-to date drug discovery for targeting Plk1 PBD, including the molecular structure and cellular functions of Plk1 PBD. Small-molecule inhibitors targeting Plk1 PBD not only provide an opportunity to specifically inhibit Plk1 activity for cancer treatment, but also unveil novel biological basis regarding the molecular recognition of Plk1 and its substrates.

Expression of polo-like kinase 1 in pre-implantation stage murine somatic cell nuclear transfer embryos

Somatic cell nuclear transfer (SCNT) has various applications in research, as well as in the medical field and animal husbandry. However, the efficiency of SCNT is low and the accurate mechanism of SCNT in murine embryo development is unreported. In general, the developmental rate of SCNT murine embryos is lower than in vivo counterparts. In previous studies, polo-like kinase 1 (Plk1) was reported to be a crucial element in cell division including centrosome maturation, cytokinesis, and spindle formation. In an initial series of experiments in this study, BI2536, a Plk1 inhibitor, was treated to in vivo-fertilized embryos and the embryos failed to develop beyond the 2-cell stage. This confirmed previous findings that Plk1 is crucial for the first mitotic division of murine embryos. Next, we investigated Plk1's localization and intensity by immunofluorescence analysis. In contrast to normally developed embryos, SCNT murine embryos that failed to develop exhibited two types of Plk1 expressions; a low Plk1 expression pattern and ectopic expression of Plk1. The results show that Plk1 has a critical role in SCNT murine embryos. In conclusion, this study demonstrated that the SCNT murine embryos fail to develop beyond the 2-cell stage, and the embryos show abnormal Plk1 expression patterns, which may one of the main causes of developmental failure of early SCNT murine embryos.

Enhanced polo-like kinase 1 expression in myelodysplastic syndromes

BACKGROUND: Cancer is characterized by uncontrolled cellular proliferation, and Polo-like kinase 1 (PLK1), a key regulator of the cell cycle, is overexpressed in many cancers, including acute leukemia and lymphoma. However, the dynamics of PLK1 transcription in myelodysplastic syndromes (MDS) are unknown. This study aimed to investigate the transcript dynamics of PLK1 and determine its role in the pathophysiology of MDS. METHODS: PLK1 mRNA obtained from the bone marrow samples of 67 patients with MDS, 16 patients with secondary acute myeloid leukemia (sAML), and 10 healthy controls were analyzed using quantitative real-time PCR and compared according to various clinical parameters. RESULTS: The median PLK1 expression levels differed slightly, but not significantly, between MDS and sAML patients [661.21 (range, 29.38–8,987.31) vs. 1,462.05 (32.22–5,734.09), respectively], but were significantly higher (P<0.001) than the levels in the healthy controls [19.0 (1.60–49.90)]. Further analyses of PLK1 levels according to the WHO classification of MDS, prognostic risk groups, karyotype risk groups, marrow blast percentage, and depth of cytopenia did not reveal any significant associations. In patients progressing to sAML, PLK1 expression levels differed significantly according to the presence or absence of resistance to hypomethylation treatment (2,470.58 vs. 415.98, P=0.03). CONCLUSION: PLK1 is upregulated in MDS patients; however, its role in the pathophysiology of MDS is unclear. Gene upregulation in cases with pharmacotherapeutic resistance warrants further investigation.

The expression and its clinical significance of PLK1 in castration-resistant prostate cancer / 天津医药

Objective To study the relationship between the expression level of PLK1 in castration-resistant prostate cancer (CRPC) tissues, and its relationship with pathological features. Methods Forty-four CRPC specimens including 28 samples from patients with prostate adenocarcinoma, 14 samples from patients with neuroendocrine prostate cancer (NEPC) and 2 samples from patients with other types of prostate cancer, and 10 normal prostatic hyperplasia specimens were collected from January 2010 to September 2016 in the Second Hospital of Tianjin Medical University. The expression levels of PLK1 in these tissues were detected by S-P immunohistochemistry. The relationship between PLK1 expression and pathologic factors was discussed. Results The positive expression of PLK1 was located in cytoplasm of carcinoma cells, and no express of PLK1 was found in benign prostatic hyperplasia tissues. The expression levels of PLK1 showed no significantly differences between different groups of age, local tumor invasion and regional nodal status, and the level of prostate-specific antigen (PSA, P>0.05). The expression level of PLK1 in patients with Gleason score>8 was higher than that in patients with Gleason score≤8. The PLK1 expression level was positively correlated with Gleason score (rs=0.441,P<0.05). Conclusion PLK1 protein is over-expressed in CRPC tissues, which can reflect the proliferation and differentiation of cancer cells and may be a potential marker of CRPC.

Research progress of PoIo-Iike kinase 1 inhibitors targeting PoIo-box domain / 中国药科大学学报

The over-expression of Polo-like kinase 1(Plk1)is critical in the producing and progressing of multi-ple human tumors and is recognized as an effective target for the development of novel anti-cancer drugs.Currently a variety of small molecules targeting ATP or substrates binding sites have entered different stages of clinical trials.Polo-box domain(PBD)is a unique domain of Plks which plays an important role in the sub-cellular location of Plks and also in the recognition of their substrates,therefore it has become an attractive target for the development of novel target-directed Plk1 inhibitors.In this paper,PBD function of Plk1 was intro-duced,the progress of small molecule and phosphoserine /phosphothreonine contained short peptide Plk1 inhibi-tors targeting PBD was summarized.Further development of this kind of inhibitors was also proposed.

Expression of polo-like kinase 1 in human renal cell carcinoma and impact of BI2536 on the cell proliferation of renal cell carcinoma A498 cell line / 中华泌尿外科杂志

Objective To investigate the expression of Polo-like kinase 1 in renal clear cell carcinoma and tissue adjacent to carcinoma;impact of BI2536 on the cell proliferation of renal clear cell carcinoma A498 cell line.Methods We select 12 cases of renal cancer Specimens of randical surgery between January 2013 and December 2014.The study included 7 male patients and 5 female patients,whose age ranged from 41 to 68 years(mean 49 years).Tumors were single and the location of tumor included 5 in left kidney,7 in right kidney.The size of renal tumor ranged from 2.1 to 6.3 cm.All patients did not have radiotherapy and chemotherapy preoperative who have no local and distant matastasis.The pathological results demonstrated renal clear cell carcinoma in 12 cases.At the same time,we collect the tissue 2 centimeters away as control,which pathological results demonstrated normal tissue.The expression of PLK1 was detected by western bloting in tissues from 12 cases of renal clear cell carcinoma and tissue adjacent to carcinoma and quantitative analysis was made.Cell proliferation of A498 cell line at the different concentrations of BI2536 were assayed by flow cytometry (0,20,40,60μg/L).Results The expression of PLK1 in renal clear cell carcinoma tissue are 0.74 ±0.2 and 0.21 ±0.13.The carcinoma tissue is higher than tissue adjacent to carcinoma (P =0.02).BI2536 act on A498 after 48 hours,the A498 cell number were arrested at G2/M phase at 0μg/L,20μg/L,40μg/L and 60μg/L were (10.28 ± 0.47) ％,(14.35 ± 0.85) ％,(20.49 ± 0.78) ％ and (23.90 ± 0.54) ％,respectively.The A498 cell number were arrested at G2/M phase increase when we incearse the concentrations of BI2536 at 48 hours (P ＜ 0.05).Conclusions The higher expression of PLK1 in renal clear cell carcinoma and the proliferation of the renal clear carcinoma cell can be repressed by BI2536 both reveal PLK1 may be used as the molecular maker and therapeutics target of renal clear cell carcinoma.

Research progress on PLK1 in castrate-resistant prostate cancer / 中国肿瘤临床

Polo-like kinase 1 (PLK1) is a highly conserved serine/threonine protein kinase that has attracted research attention be-cause it plays a critical role in mitosis regulation. PLK1 is overexpressed in 80%of human tumors, which indicates a poor prognosis in most tumors. PLK1 is one of the most promising targets for antitumor therapy because it is upregulated in castrate-resistant prostate can-cer (CRPC). This review focused on the basic structure and function of PLK1, the relationship between PLK1 and CRPC occurrence and progression, and CRPC treatment by inhibiting PLK1. This study provides a theoretical basis for the targeted molecular therapy of CRPC.

The molecular docking of 1,4-naphthoquinone derivatives as inhibitors of Polo-like kinase 1 using Molegro Virtual Docker.

Polo-like kinase 1 (Plk1) is over expressed in many types of human cancers, and has been implicated as an adverse prognostic marker for cancer patients. Plk1 is localized to its intracellular anchoring sites via its polo-box domain (PBD). The PBD of Plk1 has a crucial role in proper subcellular localization and mitotic functions of Plk1. Plk1 is the preferential target for inhibition of the mitotic processing therefore it can be chosen as drug target for the treatment of cancer. The aim of the study is to find plk1 inhibitor potential from naphthoquinone derivatives through binding free energy analysis into plk1 using molecular docking. We conducted docking simulation to naphthoquinone derivatives as ligands into plk1 as receptor. The 3D structure of plk1 was downloaded from PDB (Code ID:3THB). The structure of ligands and protein were prepared using ChemBioDrawUltra 12.0. Docking process, the interaction and binding of ligands – protein were done and visualized using software Molegro Virtual Docking.(MVD). The results showed no hydrogen bonding and electrostatic interaction between compound NO11(modified naphthoquinone) with Plk1, but this compound have more steric interaction with Phe 133, Asp 194, Glu 101, Lys 82, Cys 133 and Glu 140 of Plk1. Moldock scores of compound NO11, is -134.73 kcal/mol. It is predicted that compound NO11 has potency as lead compound to find a new anticancer candidates for possible therapeutic agents.

Research progress of the roles of Polo-like kinase 1 in cell mitosis / 肿瘤研究与临床

Polo-like kinase 1 (Plk1) is a serine/threonine kinase that is widely expressed in eukaryotic cells and a key regulator of the cell mitosis.During different stages of mitosis,the locations of Plk1 in cells are different,and can interaction with different substrates,thus it has many biological functions.This article focuses on the functions of Plk1 in different mitotic stages.

Construction of PLK1 siRNA and its effects on proliferation and apoptosis of undifferentiated human thyroid cancer cells / 中华内分泌外科杂志

Objective To study effects of polo-like kinase-1(PLK1)small interfering RNA(siRNA)on proliferation and apoptosis of undifferentiated human thyroid cancer cells.Methods 5 PLK1 siRNA(S1,S2,S3,S4 and S5)were constructed and used to transfect human thyroid cancer cell line ARO.RT-PCR was employed to pick out the most effective siRNA,which was then used to transfect ARO cell.RT-PCR and western blot were used to detect PLK1 expression in thyroid cancer cells,which were divided into different groups.MTT assay was performed to examine the effects of PLK1 siRNA on thyroid cancer cells in all groups.Apoptosis of thyroid cancer cells was observed by caspase-3 activity and TUNEL.Results All the 5 siRNA down-regulated PLK1 mRNA expression.among which S4 showed the best effect.S4 transfection could obviously inhibit proliferation of thyroid cancer cells in dose and time dependent manner.Compared with control groups,caspase-3 activity of cancer cells in s4 transfeeted group increased significantly.The effect of S4 transfection was dose and time dependent.TUNEL results showed apoptosis of cancer cells transfected by S4 siRNA was obvious and apoptosis of cells was dose-dependent.Conclusions PLK1 may play an important role in proliferation of undifferentiated thyroid carcinoma.PLK1 siRNA transfection can inhibit proliferation of throid cancer cell through apoptosis induction.

Relation between Cyclooxygenase-2 and Polo-like Kinase-1 in Non-Small Cell Lung Cancer / 결핵및호흡기질환

BACKGROUND: Elevated expression of cyclooxygenase-2 (COX-2) and Polo-like kinase-1 (PLK-1) is observed in a wide variety of cancers. Augmented expression of COX-2 and enhanced production of prostaglandin E2 (PGE2) are associated with increased tumor cell survival and malignancy; COX-2 has been implicated in the control of human non-small cell lung carcinoma (NSCLC) cell growth. PLK-1 siRNA induced the cell death of lung cancer cells and the systemic administration of PLK-1 siRNA/atelocollagen complex inhibited the growth of lung cancer in a liver metastatic murine model. COX-2 and PLK-1 are involved in proliferation and in cell cycle regulation, and there is a significant correlation between their interaction in prostate carcinoma. METHODS: In this study, we investigated the pattern of COX-2 and PLK-1 expression in NSCLC, after treatment with IL-1beta, COX-2 inhibitor and PLK-1 siRNA. RESULTS: Expression of PLK-1 was decreased in A549 COX-2 sense cells, and was increased in A549 COX-2 anti-sense cells. Knock out of PLK-1 expression by PLK-1 siRNA augmented COX-2 expression in A549 and NCl-H157 cells. When A549 and NCI-H157 cells were treated with COX-2 inhibitor on a dose-dependent basis, PLK-1 and COX-2 were reduced. However, when the expression of COX-2 was induced by IL-1beta, the production of PLK-1 decreased. CONCLUSION: These results demonstrate that COX-2 and PLK-1 are regulated and inhibited by each other in NSCLC, and suggest that these proteins have a reverse relationship in NSCLC.

Effect of Antisense RNA Targeting Polo-like Kinase 1 on Cell Growth in A549 Lung Cancer Cells / 华中科技大学学报（医学）（英德文版）

In order to investigate the effect of Polo-like kinase-1 (Plk1) depletion on cell cycle pro- gression and cell growth in lung cancer cells, a recombinant plasmid containing antisense RNA tar- getting Plk1 (pcDNA3-Plk1) was transfected into A549 cells by lipofectine. RT-PCR and Western-blot were used to detect the Plk1 gene expression. Cell proliferation was evaluated by direct cell counting and bromodeoxyuridine (BrdU) labeling. Cell cycle distribution and apoptosis were examined by flow cytometry, and the inhibition rate (IR) by vinorebline (NVB) was determined by MTT assay. The results showed that after transfection of pcDNA3-Plk1 into A549 cells, the e.xpression levels of Plk1 mRNA and protein were greatly decreased. In pcDNA3-Plk1 transfected groups, abnormal morphological changes of cells and growth inhibition were observed, and the BrdU labeling index was significantly lower than in the control groups (P＜0.05). Cells in pcDNA3-Plk1 transfected groups were arresed in G2/M phase and apoptosis was detectable 72 h post transfection. IR induced by vinorebline in pcDNA3-Plk1 transfected groups was significantly higher than in other groups.These data suggested that antisense RNA targeting Pikl could suppress the Plkl expression, and therefore, significantly inhibit cell proliferation and induce cell cycle arrest and apoptosis. Moreover,it sensitized lung cancer cells to chemotherapy.

Advance of Ser/Thr Kinase Pololike Kinase 1 (Plk1) Research / 中国生物工程杂志

Pololike kinase 1(Plk1)contain an Nterminal Ser/Thr kinase catalytic domain and a Cterminal region that contains two poloboxes.As a key regulator of multiple steps during cell cycle across eukaryotic species,many proteins interact with Plk1.Plk1 is highly expressed in malignant cells and serves as a negative prognostic marker in specific human cancer types.Plk1 is a potential target for cancer therapy.Some novel smallmolecule inhibitors of pololike kinase 1 provide novel opportunities for cancerdrug discovery,such as BI 2536,ON01910.

Measurement of the mRNA level of Polo-like kinase 1 in bronchoscopic bioptic specimens by realtime quantitative PCR / 中华检验医学杂志

0.05)and the TNM staging (P=0.55).A mild elevated compared other pathological classification was found in small cell lung cancer (0.191?0.275).Conclusions The results showed that RFQ-PCR was suitable for measurement of the mRNA level of PLKI in bronchoscopic bioptic specimens.This study suggest elevated expression of PLK1 might play a important role in development of lung cancer,so that PLK1 might be a potential tumor marker for Lung cancers.Advanced studies will be needed to clarify that PLKI mRNA level do not relate to TNM staging and pathological classification.

Effect of antisense RNA targeting Polo-like kinase 1 on cell growth in A549 lung cancer cells / 中国病理生理杂志

AIM:To investigate the effect of Polo-like kinase-1(Plk1) depletion on cell cycle progression and cell growth in lung cancer cells.METHODS:A recombinant plasmid containing antisense RNA targeting Plk1(pcDNA3-Plk1) was transfected into A549 cells by lipofectine.RT-PCR and Western blotting were used to examine Plk1 gene expression.Cell proliferation was evaluated by cell counting and BrdU labeling.Cell cycle distribution and apoptosis were examined by flow cytometry.Inhibition rate(IR) of vinorebline(NVB) was determined by MTT assay.RESULTS:After transfected with pcDNA3-Plk1 into A549 cells,the expression levels of Plk1 mRNA and protein were greatly decreased.Abnormal morphological changes of cells and growth inhibition were observed in pcDNA3-Plk1 transfected cells.The BrdU labeling index was significantly lower than that in control group(P

EXPRESSION OF Polo-LIKE KINASE 1 DURING THE DIFFERENTIATION OF CARDIOMYOCYTES IN RATS / 解剖学报

Objective To understand the mechanism of how cardiomyocytes exit from the cell cycle,we examined the expression of polo-like kinase 1(plk1) in the postnatal developmental process of cardiac myocytes. Methods Mitotic Index(MI) of cardiomyocytes was examined in the neonatal,2-week-old,4-week-old,and adult rat hearts(five cases per groups) by double immunofluorescence stained with H3P and ?-sarcomeric actin antibodies.plk1 mRNA and protein expression during the postnatal developmental process of cardiac myocytes were detected by RT-PCR and Western blot analysis in rat hearts. Results The MI of cardiomyocytes in 0-day-old hearts(0.905?0.087%) was approximately 2.4 times over that in 2-week-old hearts(0.372?0.094%)(P