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The balance of Polo-like kinase 1 in tumorigenesis


Polo-like kinase 1 (Plk1) belongs to a family of conserved serine/threonine kinases with a polo-box domain, which have similar but non-overlapping functions in the cell cycle progression. Plk1 plays a key role to ensure the normal mitosis. Interestingly, overexpression of Plk1 is associated with tumor development and could serve as a prognostic marker for many cancers. Due to Plk1 overexpression, several Plk1 inhibitors have been developed and tested for the cancer treatment. However, in a recent study, it has been suggested that down-regulation of Plk1 could also induce aneuploidy and tumor formation in vivo. Therefore, a normal level of Plk1 is important for mitosis. And caution should be taken when Plk1 inhibitors are used in the clinical trial and their side effects including tumorigenesis should be carefully evaluated.


Polo-like kinases (Plks) are serine/threonine kinases with an N-terminal kinase domain and a C-terminal polo-box domain. The domain structure of this family is evolutionary conserved from yeast to mammals[1]. In mammals, there are four different Plks that all participate in the cell cycle regulation [2]. Plk1 is the best characterized member in this group. Numerous lines of evidence demonstrate that Plk1 plays critical roles in multiple stages of mitosis (reviewed in [3]). Either up-regulated or down-regulated Plk1 could induce mitotic defects that result in aneuploidy and tumorigenesis. Therefore, balanced Plk1 levels are important for normal mitosis. In this review, we will summarize current understandings of the role of Plk1 in mitosis, with emphasis on its association with tumorigenesis.

Multiple roles of Plk1 in mitotic progression

Plkl functions in almost every stage of mitosis, as evidenced by changing of its localization during mitotic progression. Plk1 localizes at the centrosomes during inter-phase and prophase, and is found at kinetochores in pre-metaphase and metaphase. It later relocates to spindles during anaphase and finally resides at the midbody during telophase [47]. This dynamic localization of Plk1 correlates with several distinct functions of Plk1 that are through its different substrates recognition and phosphorylation during mitosis. Plk1 directly promotes mitotic entry by activating Cdc25C and Cdk1/Cyclin B complex [810]. It contributes to centrosome maturation and drives microtubule nucleation through phosphorylating Nlp, Kizuna and Asp [1114]. Plk1 facilitates kinetochore assembly and potentially regulates of spindle assembly checkpoint by interaction with INCENP, Bub1 and BubR1 [5, 1517]. Plk1 is also indispensable for the completion of cytokinesis by regulating Ect2 and RhoA [18, 19]. Consistent with the critical role of Plk1 in mitosis, Plk1-deficient mice are early embryonic lethal. Plk1-null embryos fail to pass 8-cell stage and no mitotic cells were observed in these embryos [20]. Although Plk1-null zygotes could go through three rounds of mitosis and develop to 8-cell stage, it is most likely that maternal Plk1 protein and mRNA are still sufficient for a few rounds of mitosis. Once depleting the maternal material contributed Plk1 protein, cell cycle is arrested.

Plk1 overexpression is associated with tumorigenesis

Proper cell cycle progression is critical for maintaining genomic stability. Mitosis is particularly tightly regulated as deregulated mitosis would lead to improper segregation of chromosomes. Checkpoints including G2/M checkpoint, kinetochore and spindle checkpoint have therefore evolved to ensure proper onset of mitosis and correct transmission of genetic material to daughter cells [21]. The mitotic progression is mainly promoted by cyclin-dependent kinases and further controlled by several critical mitotic kinases including Plk1 [22, 23]. Therefore, the expression level of these mitotic kinases must be tightly regulated. Overexpression of these kinases can override those mitotic checkpoints and lead to immature cell division without proper chromosome alignment and segregation, which will result in aneuploidy, one of the major causes for tumorigenesis [24, 25]. Because of this, these mitotic kinases including Plk1 are often considered as proto-oncogenes, whose overexpression is often observed in tumor cells [26]. Meanwhile, aneuploidy and tumorigenesis can also result from centrosome abnormality, particularly centrosome amplification defects [27, 28]. Centrosome duplication and maturation regulated by Plk1 occurs from late S phase to prophase [11]. Abnormal centrosome amplification may lead to multipolar spindles and results in unequal segregation of chromosomes [29]. Thus, Plk1 overexpression may also increase the centrosome size and/or centrosome number, which will also lead to improper segregation of chromosomes, aneuploidy, and tumorigenesis.

To date, overexpression of Plk1 has been observed in a number of human cancers including non-small-cell lung cancer [30], head and neck cancer [31], esophageal cancer [32, 33], gastric cancer [32, 34, 35], melanomas [36, 37], breast cancer[38], ovarian cancer [39], endometrial cancer [40], colorectal cancer [41, 42], glioma [43], papillary carcinoma [44], pancreatic cancer [45, 46], prostate cancer [47], hepatoma [48], leukemia and lymphoma [49, 50], bladder cancer [51], and thyroid cancer [52]. Many of these studies have demonstrated that Plk1 overexpression correlates with tumor progression and patient survival rate in a variety of cancers [3033, 3537, 42, 4850]. Therefore, Plk1 is proposed as a prognostic marker for human cancers.

Although Plk1 is often overexpressed in human cancers, the Plk1 gene is rarely amplified, indicating that transcriptional or post-transcriptional regulation of Plk1 are affected in cancer cells. The association of Plk1 overexpression with cancers could be explained as a result of high mitotic index of tumor cells since Plk1 levels are cell cycle-regulated with a peak during mitosis [4, 7]. Indeed, early studies of Plk1 in different fetal and adult tissues have shown that Plk1 levels are much higher in thymus, spleen and testis, which have more proliferating cells [5355]. However, Plk1 overexpression has been indicated as the cause of tumor formation instead of being the consequence of high mitotic index during tumor cell proliferation. Overexpression of Plk1 in NIH3T3 fibroblasts transformed the cells into oncogenic foci in soft agar and more importantly lead to tumor formation when injected into nude mice [56].

Development of Plk1 inhibitors

Since Plk1 is considered as a "proto-oncogene", inhibition of Plk1 could be an effective treatment for cancers. Several strategies of inhibiting Plk1 activity have thus been tested in cancer therapeutic trials. One of the strategies is to deplete the expression of Plk1 by using anti-sense oligonucleotides (ASO) or small interfering RNA (siRNA) to block Plk1 translation or transcription. This rationale comes from the effect of Plk1 depletion in cell cultures, which leads to mitotic arrest and apoptosis of the cells [57, 58]. To date, several groups have also shown successful suppression of tumor growth by this approach in vivo. For example, intravenous injection of Plk1 ASO significantly suppressed growth of A549 cells in tumor xenografts [59]. Similarly, Intravesical administration of Plk1 siRNA suppressed bladder cancer growth in an orthotopic bladder cancer mouse model [60]. Plasmid-based U6 promoter-driven short hairpin RNA has also been demonstrated to be effective in suppressing growth of HeLa S3 xenografts [61]. However, due to the intrinsic problems including dose-limiting side effects, inadequate penetration into the tumor tissues, and degradation by endogenous nucleases, it is difficult to achieve a consistently high efficacy [62, 63]. Optimization of the delivery system is ongoing, for example using ASO-loaded HSA nanoparticles [64].

Using small molecules to inhibit Plk1 is another approach, as these molecules are easier to be delivered into cells and are less likely to be degraded. For most chemical inhibitors, they are designed to suppress important functional domains. For Plk1, one important domain is the serine/threonine kinase domain at the N-terminus. Same as other serine/threonine kinases, the activity of Plk1 kinase domain requires ATP. Thus, ATP analogues have been designed and screened for inhibiting Plk1. The first identified inhibitor of this kind is scytonemin isolated from cyanobacteria with an IC50 of 2 μM [65]. Recently, a much more specific ATP competitor, BI 2536, has been identified. It inhibits the kinase activity of Plk1 with an IC50 of only 0.83 nM. More importantly, this molecule displayed 1000-fold selectivity for Plk1 over 63 other kinases tested [66, 67]. BI 2526 not only induced mitotic arrest and apoptosis in a number of tumor cells, but also suppressed the growth of human tumor xenografts in nude mice [66]. Currently, a phase I clinical trial is ongoing with the treatment of advanced solid tumors [68]. Besides BI 2526, several other compounds including thiophene benzimidazole compound 1 and pyrimidine derivative DAP-81 have also been shown to specifically inhibit Plk1 activity [69, 70].

Besides ATP analogs, several non-ATP competitors were identified to block substrates binding to Plk1 kinase domain. For example, ON01910 inhibits Plk1 effectively with an IC50 of 9–10 nM [71]. This drug potently induced apoptosis in 151 tumor cell lines tested and inhibited tumor growth of three human tumor xenografts in nude mice. Currently, this drug is under evaluation in phase I clinical trials [72]. Similarly, a non-ATP competitive inhibitor TAL was recently identified that specifically inhibits Plk1 over 93 other kinases with an IC50 of around 19 nM [73]. Using a structural-guided approach, a non-ATP competitive inhibitor cyclapolin 1 was also identified to inhibit Plk1 with an IC50 of 20 nM [74].

Except the kinase domain, the other important domain of Plk1 is the C-terminal polo-box domain (PBD). This domain is a phospho-amino acid binding motif [10, 75, 76] that is essential for the substrate recognition and localization of Plk1 to centrosomes, kinetochores, and the midbody [77, 78]. Chemical compounds that block the PBD would thus block the functions of Plk1. One advantage is that the PBD is not present in kinases other than Plks. Therefore, it is unlikely that small molecules targeting the PBD will affect other kinases. Based on this hypothesis, the natural product thymoquinone and the synthetic thymoquinone derivative Poloxin were identified that inhibited Plk1 by interfering the PBD [79]. Although with less potency, these drugs provided the proof of the principle that targeting PBD is a promising approach.

One concern for all Plk1 inhibitors is that they inhibit other Plks with similar potencies, most likely due to the structural similarities between these four family members. For example, besides inhibiting Plk1 with IC50 of 0.83 nM, BI 2536 also inhibit Plk2 and Plk3 with IC50 3.5 nM and 9 nM respectively [66]. Such broad inhibition of all Plks may have unexpected side effects as different Plks have none overlapping roles in mitosis, and not all Plks are overexpressed in cancers [80, 81].

Loss of Plk1 also leads to tumor formation

Paradoxically, loss of Plk1 is also associated with tumor formation. Several missense mutations of Plk1 have been identified in different cancer cell lines with various tissue origins [82]. These mutations locate at the C-terminal PBD and suppress the interaction between Plk1 and HSP90, a molecular chaperon that functions in protein folding [83]. As a result, mutant Plk1 is unstable without the chaperon, which leads to low expression levels of Plk1 in these cell lines. Since Plk1 is a key mitotic kinase, the reduction of Plk1 may also induce mitotic defects that lead to aneuploidy and tumorigenesis. This possibility has been proven by a recent in vivo study [20]. In this study, Plk1 heterozygous mice have been generated, in which the expression level of Plk1 was significantly decreased. A cohort of Plk1 wild type and heterozygous mice were maintained and the tumor development was monitored. Surprisingly, 30% of Plk1 heterozygous mice developed tumors at an average of 13–14 months old, and this was a 3-fold increase of tumor incidence compared with that in wild type mice. The major tumor type is lymphoma, probably due to the rapid proliferation of lymphocytes and the requirement for high expression of Plk1 to maintain the cell proliferation [55]. Moreover, correlated with the tumor phenotype, analysis of pre-malignant splenocytes displayed elevated aneuploidy in Plk1 heterozygous mice. Considering the importance of Plk1 in every stage of mitosis, reduced Plk1 levels might not only delay centrosome maturation and mitotic entry but also cause improper segregation of chromosomes and arrest cytokinesis. These events will eventually lead to aneuploidy and tumorigenesis. Thus, Plk1 can also be considered as a "haploinsufficient tumor repressor".

The tumorigenesis induced by either overexpression or down-regulation of Plk1 suggests the level of Plk1 has to be tightly regulated, which reflects its critical role in mitotic progression. Excessive Plk1 will override the mitotic checkpoint, amplify the centrosome abnormally, and chromosomes will segregate without proper alignment or unequally. Insufficient Plk1 will also leads to mitotic delay and improper separation of chromosome. In both scenarios, aneuploidy and tumors will occur. Similar associations of tumorigenesis with aberrant expression of other Plks and even other mitotic kinases were also observed [26]. For example, the expression of Plk3 is down-regulated in several human cancers [8486] and Plk3 is therefore considered as a tumor-suppressor gene. Consistently, Plk3 knockout mice are viable and develop tumors in various organs in advanced stage [87]. Plk4 is another potential tumor suppressing gene residing at chromosome 4q28 in human, a region where loss of heterozygosity (LOH) is common in hepatoma samples [88]. Plk4-null mice are embryonic lethal and Plk4 heterozygous mice display 15-fold increase in incidence of liver and lung cancers than that of wild type mice [89]. These all suggest that the level of these kinases needs to be tightly regulated.

Like Plk1, Aurora A, is another multi-functional kinase involved in all stages of mitosis [90, 91]. Overexpression of Aurora A has been reported in a number of cancers [92], and chemical compounds have been developed to target Aurora A in cancer therapeutic trials. Similar as Plk1, overexpression of Aurora A suppresses the mitotic checkpoint, induces various mitotic defects and transformation of fibroblasts both in vitro and in vivo. Moreover, like Plk1-null mice, Aurora A knockout mice fail to survive after blastocyst stage [93, 94]. More importantly, Aurora A heterozygous mice with reduced Aurora A level are also tumor prone with a significant increased incidence of lymphoma. And lymphocytes from Aurora A heterozygous mice display elevated aneuploidy [93]. The similar phenotypes between Plk1 and Aurora A knockout mice suggest that these two mitotic kinases work in a similar pathway. Indeed, recent reports suggest that Plk1 is actually activated by Aurora A and its cofactor Bora before it activates CDK1 and promotes mitotic entry [95, 96]. Again, the similar tumor phenotypes of Plk1 and Aurora A heterozygous mice suggest that balanced mitotic kinases are important for maintaining genomic stability. Reducing the levels of these mitotic kinases long term may induce tumorigenesis. Since a few drugs targeting Plks and Aurora kinases are currently in the clinical trails for cancer treatment, long term side effects including secondary tumor formation should be carefully evaluated.

Concluding remarks

Plk1 is a critical kinase with multiple functions during mitotic progression. Its expression level has to be precisely regulated. Either overexpression or down-regulation of Plk1 will lead to tumorigenesis. Considering several ongoing clinical trials using Plk1 inhibitors, the side effects of these drugs in inducing genomic instability should be carefully observed.


  1. 1.

    Fenton B, Glover DM: A conserved mitotic kinase active at late anaphase-telophase in syncytial Drosophila embryos. Nature 1993, 363(6430):637–640.

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Weerdt BC, Medema RH: Polo-like kinases: a team in control of the division. Cell Cycle 2006, 5(8):853–864.

    Article  PubMed  Google Scholar 

  3. 3.

    Petronczki M, Lenart P, Peters JM: Polo on the Rise-from Mitotic Entry to Cytokinesis with Plk1. Dev Cell 2008, 14(5):646–659.

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Golsteyn RM, Mundt KE, Fry AM, Nigg EA: Cell cycle regulation of the activity and subcellular localization of Plk1, a human protein kinase implicated in mitotic spindle function. J Cell Biol 1995, 129(6):1617–1628.

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Arnaud L, Pines J, Nigg EA: GFP tagging reveals human Polo-like kinase 1 at the kinetochore/centromere region of mitotic chromosomes. Chromosoma 1998, 107(6–7):424–429.

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Wianny F, Tavares A, Evans MJ, Glover DM, Zernicka-Goetz M: Mouse polo-like kinase 1 associates with the acentriolar spindle poles, meiotic chromosomes and spindle midzone during oocyte maturation. Chromosoma 1998, 107(6–7):430–439.

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Hamanaka R, Smith MR, O'Connor PM, Maloid S, Mihalic K, Spivak JL, Longo DL, Ferris DK: Polo-like kinase is a cell cycle-regulated kinase activated during mitosis. J Biol Chem 1995, 270(36):21086–21091.

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Kumagai A, Dunphy WG: Purification and molecular cloning of Plx1, a Cdc25-regulatory kinase from Xenopus egg extracts. Science (New York, NY) 1996, 273(5280):1377–1380.

    CAS  Article  Google Scholar 

  9. 9.

    Toyoshima-Morimoto F, Taniguchi E, Nishida E: Plk1 promotes nuclear translocation of human Cdc25C during prophase. EMBO Rep 2002, 3(4):341–348.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  10. 10.

    Elia AE, Rellos P, Haire LF, Chao JW, Ivins FJ, Hoepker K, Mohammad D, Cantley LC, Smerdon SJ, Yaffe MB: The molecular basis for phosphodependent substrate targeting and regulation of Plks by the Polo-box domain. Cell 2003, 115(1):83–95.

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Lane HA, Nigg EA: Antibody microinjection reveals an essential role for human polo-like kinase 1 (Plk1) in the functional maturation of mitotic centrosomes. J Cell Biol 1996, 135(6 Pt 2):1701–1713.

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Casenghi M, Meraldi P, Weinhart U, Duncan PI, Korner R, Nigg EA: Polo-like kinase 1 regulates Nlp, a centrosome protein involved in microtubule nucleation. Developmental cell 2003, 5(1):113–125.

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Oshimori N, Ohsugi M, Yamamoto T: The Plk1 target Kizuna stabilizes mitotic centrosomes to ensure spindle bipolarity. Nature cell biology 2006, 8(10):1095–1101.

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    do Carmo Avides M, Tavares A, Glover DM: Polo kinase and Asp are needed to promote the mitotic organizing activity of centrosomes. Nature cell biology 2001, 3(4):421–424.

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Elowe S, Hummer S, Uldschmid A, Li X, Nigg EA: Tension-sensitive Plk1 phosphorylation on BubR1 regulates the stability of kinetochore microtubule interactions. Genes & development 2007, 21(17):2205–2219.

    CAS  Article  Google Scholar 

  16. 16.

    Goto H, Kiyono T, Tomono Y, Kawajiri A, Urano T, Furukawa K, Nigg EA, Inagaki M: Complex formation of Plk1 and INCENP required for metaphase-anaphase transition. Nature cell biology 2006, 8(2):180–187.

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Qi W, Tang Z, Yu H: Phosphorylation- and polo-box-dependent binding of Plk1 to Bub1 is required for the kinetochore localization of Plk1. Molecular biology of the cell 2006, 17(8):3705–3716.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  18. 18.

    Mundt KE, Golsteyn RM, Lane HA, Nigg EA: On the regulation and function of human polo-like kinase 1 (PLK1): effects of overexpression on cell cycle progression. Biochem Biophys Res Commun 1997, 239(2):377–385.

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Carmena M, Riparbelli MG, Minestrini G, Tavares AM, Adams R, Callaini G, Glover DM: Drosophila polo kinase is required for cytokinesis. J Cell Biol 1998, 143(3):659–671.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  20. 20.

    Lu LY, Wood JL, Minter-Dykhouse K, Ye L, Saunders TL, Yu X, Chen J: Polo-like kinase 1 is essential for early embryonic development and tumor suppression. Mol Cell Biol 2008, 28(22):6870–6876.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  21. 21.

    Musacchio A, Salmon ED: The spindle-assembly checkpoint in space and time. Nat Rev Mol Cell Biol 2007, 8(5):379–393.

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Sullivan M, Morgan DO: Finishing mitosis, one step at a time. Nat Rev Mol Cell Biol 2007, 8(11):894–903.

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Ferrari S: Protein kinases controlling the onset of mitosis. Cell Mol Life Sci 2006, 63(7–8):781–795.

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Weaver BA, Cleveland DW: Does aneuploidy cause cancer? Curr Opin Cell Biol 2006, 18(6):658–667.

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Kops GJ, Weaver BA, Cleveland DW: On the road to cancer: aneuploidy and the mitotic checkpoint. Nat Rev Cancer 2005, 5(10):773–785.

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Malumbres M, Barbacid M: Cell cycle kinases in cancer. Curr Opin Genet Dev 2007, 17(1):60–65.

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Lingle WL, Barrett SL, Negron VC, D'Assoro AB, Boeneman K, Liu W, Whitehead CM, Reynolds C, Salisbury JL: Centrosome amplification drives chromosomal instability in breast tumor development. Proc Natl Acad Sci USA 2002, 99(4):1978–1983.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  28. 28.

    Pihan GA, Wallace J, Zhou Y, Doxsey SJ: Centrosome abnormalities and chromosome instability occur together in pre-invasive carcinomas. Cancer Res 2003, 63(6):1398–1404.

    CAS  PubMed  Google Scholar 

  29. 29.

    Doxsey S, Zimmerman W, Mikule K: Centrosome control of the cell cycle. Trends Cell Biol 2005, 15(6):303–311.

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    Wolf G, Elez R, Doermer A, Holtrich U, Ackermann H, Stutte HJ, Altmannsberger HM, Rubsamen-Waigmann H, Strebhardt K: Prognostic significance of polo-like kinase (PLK) expression in non-small cell lung cancer. Oncogene 1997, 14(5):543–549.

    CAS  Article  PubMed  Google Scholar 

  31. 31.

    Knecht R, Elez R, Oechler M, Solbach C, von Ilberg C, Strebhardt K: Prognostic significance of polo-like kinase (PLK) expression in squamous cell carcinomas of the head and neck. Cancer Res 1999, 59(12):2794–2797.

    CAS  PubMed  Google Scholar 

  32. 32.

    Tokumitsu Y, Mori M, Tanaka S, Akazawa K, Nakano S, Niho Y: Prognostic significance of polo-like kinase expression in esophageal carcinoma. Int J Oncol 1999, 15(4):687–692.

    CAS  PubMed  Google Scholar 

  33. 33.

    Feng YB, Lin DC, Shi ZZ, Wang XC, Shen XM, Zhang Y, Du XL, Luo ML, Xu X, Han YL, et al.: Overexpression of PLK1 is associated with poor survival by inhibiting apoptosis via enhancement of survivin level in esophageal squamous cell carcinoma. Int J Cancer 2009, 124(3):578–588.

    CAS  Article  PubMed  Google Scholar 

  34. 34.

    Jang YJ, Kim YS, Kim WH: Oncogenic effect of Polo-like kinase 1 expression in human gastric carcinomas. Int J Oncol 2006, 29(3):589–594.

    CAS  PubMed  Google Scholar 

  35. 35.

    Kanaji S, Saito H, Tsujitani S, Matsumoto S, Tatebe S, Kondo A, Ozaki M, Ito H, Ikeguchi M: Expression of polo-like kinase 1 (PLK1) protein predicts the survival of patients with gastric carcinoma. Oncology 2006, 70(2):126–133.

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Strebhardt K, Kneisel L, Linhart C, Bernd A, Kaufmann R: Prognostic value of pololike kinase expression in melanomas. Jama 2000, 283(4):479–480.

    CAS  Article  PubMed  Google Scholar 

  37. 37.

    Kneisel L, Strebhardt K, Bernd A, Wolter M, Binder A, Kaufmann R: Expression of polo-like kinase (PLK1) in thin melanomas: a novel marker of metastatic disease. J Cutan Pathol 2002, 29(6):354–358.

    Article  PubMed  Google Scholar 

  38. 38.

    Wolf G, Hildenbrand R, Schwar C, Grobholz R, Kaufmann M, Stutte HJ, Strebhardt K, Bleyl U: Polo-like kinase: a novel marker of proliferation: correlation with estrogen-receptor expression in human breast cancer. Pathol Res Pract 2000, 196(11):753–759.

    CAS  PubMed  Google Scholar 

  39. 39.

    Weichert W, Denkert C, Schmidt M, Gekeler V, Wolf G, Kobel M, Dietel M, Hauptmann S: Polo-like kinase isoform expression is a prognostic factor in ovarian carcinoma. Br J Cancer 2004, 90(4):815–821.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  40. 40.

    Takai N, Miyazaki T, Fujisawa K, Nasu K, Hamanaka R, Miyakawa I: Polo-like kinase (PLK) expression in endometrial carcinoma. Cancer Lett 2001, 169(1):41–49.

    CAS  Article  PubMed  Google Scholar 

  41. 41.

    Takahashi T, Sano B, Nagata T, Kato H, Sugiyama Y, Kunieda K, Kimura M, Okano Y, Saji S: Polo-like kinase 1 (PLK1) is overexpressed in primary colorectal cancers. Cancer Sci 2003, 94(2):148–152.

    CAS  Article  PubMed  Google Scholar 

  42. 42.

    Weichert W, Kristiansen G, Schmidt M, Gekeler V, Noske A, Niesporek S, Dietel M, Denkert C: Polo-like kinase 1 expression is a prognostic factor in human colon cancer. World J Gastroenterol 2005, 11(36):5644–5650.

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  43. 43.

    Dietzmann K, Kirches E, von B, Jachau K, Mawrin C: Increased human polo-like kinase-1 expression in gliomas. J Neurooncol 2001, 53(1):1–11.

    CAS  Article  PubMed  Google Scholar 

  44. 44.

    Ito Y, Miyoshi E, Sasaki N, Kakudo K, Yoshida H, Tomoda C, Uruno T, Takamura Y, Miya A, Kobayashi K, et al.: Polo-like kinase 1 overexpression is an early event in the progression of papillary carcinoma. Br J Cancer 2004, 90(2):414–418.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  45. 45.

    Gray PJ Jr, Bearss DJ, Han H, Nagle R, Tsao MS, Dean N, Von Hoff DD: Identification of human polo-like kinase 1 as a potential therapeutic target in pancreatic cancer. Mol Cancer Ther 2004, 3(5):641–646.

    CAS  PubMed  Google Scholar 

  46. 46.

    Weichert W, Schmidt M, Jacob J, Gekeler V, Langrehr J, Neuhaus P, Bahra M, Denkert C, Dietel M, Kristiansen G: Overexpression of Polo-like kinase 1 is a common and early event in pancreatic cancer. Pancreatology 2005, 5(2–3):259–265.

    CAS  Article  PubMed  Google Scholar 

  47. 47.

    Weichert W, Schmidt M, Gekeler V, Denkert C, Stephan C, Jung K, Loening S, Dietel M, Kristiansen G: Polo-like kinase 1 is overexpressed in prostate cancer and linked to higher tumor grades. Prostate 2004, 60(3):240–245.

    CAS  Article  PubMed  Google Scholar 

  48. 48.

    Yamada S, Ohira M, Horie H, Ando K, Takayasu H, Suzuki Y, Sugano S, Hirata T, Goto T, Matsunaga T, et al.: Expression profiling and differential screening between hepatoblastomas and the corresponding normal livers: identification of high expression of the PLK1 oncogene as a poor-prognostic indicator of hepatoblastomas. Oncogene 2004, 23(35):5901–5911.

    CAS  Article  PubMed  Google Scholar 

  49. 49.

    Mito K, Kashima K, Kikuchi H, Daa T, Nakayama I, Yokoyama S: Expression of Polo-Like Kinase (PLK1) in non-Hodgkin's lymphomas. Leuk Lymphoma 2005, 46(2):225–231.

    CAS  Article  PubMed  Google Scholar 

  50. 50.

    Liu L, Zhang M, Zou P: Expression of PLK1 and survivin in diffuse large B-cell lymphoma. Leuk Lymphoma 2007, 48(11):2179–2183.

    CAS  Article  PubMed  Google Scholar 

  51. 51.

    Yamamoto Y, Matsuyama H, Kawauchi S, Matsumoto H, Nagao K, Ohmi C, Sakano S, Furuya T, Oga A, Naito K, et al.: Overexpression of polo-like kinase 1 (PLK1) and chromosomal instability in bladder cancer. Oncology 2006, 70(3):231–237.

    Article  PubMed  Google Scholar 

  52. 52.

    Salvatore G, Nappi TC, Salerno P, Jiang Y, Garbi C, Ugolini C, Miccoli P, Basolo F, Castellone MD, Cirafici AM, et al.: A cell proliferation and chromosomal instability signature in anaplastic thyroid carcinoma. Cancer Res 2007, 67(21):10148–10158.

    CAS  Article  PubMed  Google Scholar 

  53. 53.

    Hamanaka R, Maloid S, Smith MR, O'Connell CD, Longo DL, Ferris DK: Cloning and characterization of human and murine homologues of the Drosophila polo serine-threonine kinase. Cell Growth Differ 1994, 5(3):249–257.

    CAS  PubMed  Google Scholar 

  54. 54.

    Holtrich U, Wolf G, Brauninger A, Karn T, Bohme B, Rubsamen-Waigmann H, Strebhardt K: Induction and down-regulation of PLK, a human serine/threonine kinase expressed in proliferating cells and tumors. Proc Natl Acad Sci USA 1994, 91(5):1736–1740.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  55. 55.

    Golsteyn RM, Schultz SJ, Bartek J, Ziemiecki A, Ried T, Nigg EA: Cell cycle analysis and chromosomal localization of human Plk1, a putative homologue of the mitotic kinases Drosophila polo and Saccharomyces cerevisiae Cdc5. J Cell Sci 1994, 107(Pt 6):1509–1517.

    CAS  PubMed  Google Scholar 

  56. 56.

    Smith MR, Wilson ML, Hamanaka R, Chase D, Kung H, Longo DL, Ferris DK: Malignant transformation of mammalian cells initiated by constitutive expression of the polo-like kinase. Biochem Biophys Res Commun 1997, 234(2):397–405.

    CAS  Article  PubMed  Google Scholar 

  57. 57.

    Spankuch-Schmitt B, Bereiter-Hahn J, Kaufmann M, Strebhardt K: Effect of RNA silencing of polo-like kinase-1 (PLK1) on apoptosis and spindle formation in human cancer cells. J Natl Cancer Inst 2002, 94(24):1863–1877.

    CAS  Article  PubMed  Google Scholar 

  58. 58.

    Liu X, Erikson RL: Polo-like kinase (Plk)1 depletion induces apoptosis in cancer cells. Proc Natl Acad Sci USA 2003, 100(10):5789–5794.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  59. 59.

    Spankuch-Schmitt B, Wolf G, Solbach C, Loibl S, Knecht R, Stegmuller M, von Minckwitz G, Kaufmann M, Strebhardt K: Downregulation of human polo-like kinase activity by antisense oligonucleotides induces growth inhibition in cancer cells. Oncogene 2002, 21(20):3162–3171.

    CAS  Article  PubMed  Google Scholar 

  60. 60.

    Nogawa M, Yuasa T, Kimura S, Tanaka M, Kuroda J, Sato K, Yokota A, Segawa H, Toda Y, Kageyama S, et al.: Intravesical administration of small interfering RNA targeting PLK-1 successfully prevents the growth of bladder cancer. J Clin Invest 2005, 115(4):978–985.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  61. 61.

    Spankuch B, Matthess Y, Knecht R, Zimmer B, Kaufmann M, Strebhardt K: Cancer inhibition in nude mice after systemic application of U6 promoter-driven short hairpin RNAs against PLK1. J Natl Cancer Inst 2004, 96(11):862–872.

    Article  PubMed  CAS  Google Scholar 

  62. 62.

    Zhang C, Pei J, Kumar D, Sakabe I, Boudreau HE, Gokhale PC, Kasid UN: Antisense oligonucleotides: target validation and development of systemically delivered therapeutic nanoparticles. Methods Mol Biol 2007, 361: 163–185.

    CAS  Article  PubMed  Google Scholar 

  63. 63.

    Jason TL, Koropatnick J, Berg RW: Toxicology of antisense therapeutics. Toxicol Appl Pharmacol 2004, 201(1):66–83.

    CAS  Article  PubMed  Google Scholar 

  64. 64.

    Spankuch B, Steinhauser I, Wartlick H, Kurunci-Csacsko E, Strebhardt KI, Langer K: Downregulation of Plk1 expression by receptor-mediated uptake of antisense oligonucleotide-loaded nanoparticles. Neoplasia 2008, 10(3):223–234.

    PubMed Central  Article  PubMed  CAS  Google Scholar 

  65. 65.

    Stevenson CS, Capper EA, Roshak AK, Marquez B, Eichman C, Jackson JR, Mattern M, Gerwick WH, Jacobs RS, Marshall LA: The identification and characterization of the marine natural product scytonemin as a novel antiproliferative pharmacophore. J Pharmacol Exp Ther 2002, 303(2):858–866.

    CAS  Article  PubMed  Google Scholar 

  66. 66.

    Steegmaier M, Hoffmann M, Baum A, Lenart P, Petronczki M, Krssak M, Gurtler U, Garin-Chesa P, Lieb S, Quant J, et al.: BI a potent and selective inhibitor of polo-like kinase 1, inhibits tumor growth in vivo. Curr Biol 2007, 17(4):316–322.

    CAS  Article  PubMed  Google Scholar 

  67. 67.

    Lenart P, Petronczki M, Steegmaier M, Di Fiore B, Lipp JJ, Hoffmann M, Rettig WJ, Kraut N, Peters JM: The small-molecule inhibitor BI 2536 reveals novel insights into mitotic roles of polo-like kinase 1. Curr Biol 2007, 17(4):304–315.

    CAS  Article  PubMed  Google Scholar 

  68. 68.

    Mross K, Frost A, Steinbild S, Hedbom S, Rentschler J, Kaiser R, Rouyrre N, Trommeshauser D, Hoesl CE, Munzert G: Phase I dose escalation and pharmacokinetic study of BI a novel Polo-like kinase 1 inhibitor, in patients with advanced solid tumors. J Clin Oncol 2536, 26(34):5511–5517.

    Article  CAS  Google Scholar 

  69. 69.

    Lansing TJ, McConnell RT, Duckett DR, Spehar GM, Knick VB, Hassler DF, Noro N, Furuta M, Emmitte KA, Gilmer TM, et al.: In vitro biological activity of a novel small-molecule inhibitor of polo-like kinase 1. Mol Cancer Ther 2007, 6(2):450–459.

    CAS  Article  PubMed  Google Scholar 

  70. 70.

    Peters U, Cherian J, Kim JH, Kwok BH, Kapoor TM: Probing cell-division phenotype space and Polo-like kinase function using small molecules. Nat Chem Biol 2006, 2(11):618–626.

    CAS  Article  PubMed  Google Scholar 

  71. 71.

    Gumireddy K, Reddy MV, Cosenza SC, Boominathan R, Baker SJ, Papathi N, Jiang J, Holland J, Reddy EP: ON0 a non-ATP-competitive small molecule inhibitor of Plk1, is a potent anticancer agent. Cancer Cell 1910, 7(3):275–286.

    Article  CAS  Google Scholar 

  72. 72.

    Jimeno A, Li J, Messersmith WA, Laheru D, Rudek MA, Maniar M, Hidalgo M, Baker SD, Donehower RC: Phase I study of ON 01910.Na, a novel modulator of the Polo-like kinase 1 pathway, in adult patients with solid tumors. J Clin Oncol 2008, 26(34):5504–5510.

    CAS  Article  PubMed  Google Scholar 

  73. 73.

    Santamaria A, Neef R, Eberspacher U, Eis K, Husemann M, Mumberg D, Prechtl S, Schulze V, Siemeister G, Wortmann L, et al.: Use of the novel Plk1 inhibitor ZK-thiazolidinone to elucidate functions of Plk1 in early and late stages of mitosis. Mol Biol Cell 2007, 18(10):4024–4036.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  74. 74.

    McInnes C, Mazumdar A, Mezna M, Meades C, Midgley C, Scaerou F, Carpenter L, Mackenzie M, Taylor P, Walkinshaw M, et al.: Inhibitors of Polo-like kinase reveal roles in spindle-pole maintenance. Nat Chem Biol 2006, 2(11):608–617.

    CAS  Article  PubMed  Google Scholar 

  75. 75.

    Elia AE, Cantley LC, Yaffe MB: Proteomic screen finds pSer/pThr-binding domain localizing Plk1 to mitotic substrates. Science 2003, 299(5610):1228–1231.

    CAS  Article  PubMed  Google Scholar 

  76. 76.

    Cheng KY, Lowe ED, Sinclair J, Nigg EA, Johnson LN: The crystal structure of the human polo-like kinase-1 polo box domain and its phospho-peptide complex. Embo J 2003, 22(21):5757–5768.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  77. 77.

    Jang YJ, Lin CY, Ma S, Erikson RL: Functional studies on the role of the C-terminal domain of mammalian polo-like kinase. Proc Natl Acad Sci USA 2002, 99(4):1984–1989.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  78. 78.

    Seong YS, Kamijo K, Lee JS, Fernandez E, Kuriyama R, Miki T, Lee KS: A spindle checkpoint arrest and a cytokinesis failure by the dominant-negative polo-box domain of Plk1 in U-2 OS cells. J Biol Chem 2002, 277(35):32282–32293.

    CAS  Article  PubMed  Google Scholar 

  79. 79.

    Reindl W, Yuan J, Kramer A, Strebhardt K, Berg T: Inhibition of polo-like kinase 1 by blocking polo-box domain-dependent protein-protein interactions. Chem Biol 2008, 15(5):459–466.

    CAS  Article  PubMed  Google Scholar 

  80. 80.

    Takai N, Hamanaka R, Yoshimatsu J, Miyakawa I: Polo-like kinases (Plks) and cancer. Oncogene 2005, 24(2):287–291.

    CAS  Article  PubMed  Google Scholar 

  81. 81.

    Eckerdt F, Yuan J, Strebhardt K: Polo-like kinases and oncogenesis. Oncogene 2005, 24(2):267–276.

    CAS  Article  PubMed  Google Scholar 

  82. 82.

    Simizu S, Osada H: Mutations in the Plk gene lead to instability of Plk protein in human tumour cell lines. Nat Cell Biol 2000, 2(11):852–854.

    CAS  Article  PubMed  Google Scholar 

  83. 83.

    Buchner J: Hsp90 & Co. – a holding for folding. Trends Biochem Sci 1999, 24(4):136–141.

    CAS  Article  PubMed  Google Scholar 

  84. 84.

    Li B, Ouyang B, Pan H, Reissmann PT, Slamon DJ, Arceci R, Lu L, Dai W: Prk, a cytokine-inducible human protein serine/threonine kinase whose expression appears to be down-regulated in lung carcinomas. The Journal of biological chemistry 1996, 271(32):19402–19408.

    CAS  Article  PubMed  Google Scholar 

  85. 85.

    Dai W, Li Y, Ouyang B, Pan H, Reissmann P, Li J, Wiest J, Stambrook P, Gluckman JL, Noffsinger A, et al.: PRK, a cell cycle gene localized to 8p21, is downregulated in head and neck cancer. Genes, chromosomes & cancer 2000, 27(3):332–336.

    CAS  Article  Google Scholar 

  86. 86.

    Dai W, Liu T, Wang Q, Rao CV, Reddy BS: Down-regulation of PLK3 gene expression by types and amount of dietary fat in rat colon tumors. International journal of oncology 2002, 20(1):121–126.

    CAS  PubMed  Google Scholar 

  87. 87.

    Yang Y, Bai J, Shen R, Brown SA, Komissarova E, Huang Y, Jiang N, Alberts GF, Costa M, Lu L, et al.: Polo-like kinase 3 functions as a tumor suppressor and is a negative regulator of hypoxia-inducible factor-1 alpha under hypoxic conditions. Cancer Res 2008, 68(11):4077–4085.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  88. 88.

    Hammond C, Jeffers L, Carr BI, Simon D: Multiple genetic alterations, 4q28, a new suppressor region, and potential gender differences in human hepatocellular carcinoma. Hepatology (Baltimore, Md) 1999, 29(5):1479–1485.

    CAS  Article  Google Scholar 

  89. 89.

    Ko MA, Rosario CO, Hudson JW, Kulkarni S, Pollett A, Dennis JW, Swallow CJ: Plk4 haploinsufficiency causes mitotic infidelity and carcinogenesis. Nature genetics 2005, 37(8):883–888.

    CAS  Article  PubMed  Google Scholar 

  90. 90.

    Brittle AL, Ohkura H: Centrosome maturation: Aurora lights the way to the poles. Curr Biol 2005, 15(21):R880–882.

    CAS  Article  PubMed  Google Scholar 

  91. 91.

    Carmena M, Earnshaw WC: The cellular geography of aurora kinases. Nature reviews 2003, 4(11):842–854.

    CAS  Article  PubMed  Google Scholar 

  92. 92.

    Marumoto T, Zhang D, Saya H: Aurora-A – a guardian of poles. Nat Rev Cancer 2005, 5(1):42–50.

    CAS  Article  PubMed  Google Scholar 

  93. 93.

    Lu LY, Wood JL, Ye L, Minter-Dykhouse K, Saunders TL, Yu X, Chen J: Aurora A is essential for early embryonic development and tumor suppression. J Biol Chem 2008, 283(46):31785–31790.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  94. 94.

    Sasai K, Parant JM, Brandt ME, Carter J, Adams HP, Stass SA, Killary AM, Katayama H, Sen S: Targeted disruption of Aurora A causes abnormal mitotic spindle assembly, chromosome misalignment and embryonic lethality. Oncogene 2008, 27(29):4122–4127.

    CAS  Article  PubMed  Google Scholar 

  95. 95.

    Macurek L, Lindqvist A, Lim D, Lampson MA, Klompmaker R, Freire R, Clouin C, Taylor SS, Yaffe MB, Medema RH: Polo-like kinase-1 is activated by aurora A to promote checkpoint recovery. Nature 2008, 455(7209):119–123.

    CAS  Article  PubMed  Google Scholar 

  96. 96.

    Seki A, Coppinger JA, Jang CY, Yates JR, Fang G: Bora and the kinase Aurora a cooperatively activate the kinase Plk1 and control mitotic entry. Science 2008, 320(5883):1655–1658.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

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This work was supported in part by the American Cancer Society (RSG-08-125-01-CCG to XY). XY is a recipient of AACR-Susan G. Komen for the Cure Cancer Development Award, and is supported by the Developmental fund from the University of Michigan Cancer Center.

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Correspondence to Xiaochun Yu.

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The authors declare that they have no competing interests.

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LL and XY contributed to the discussion and preparation of this manuscript. Both the authors read and approved the final manuscript.

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Lu, LY., Yu, X. The balance of Polo-like kinase 1 in tumorigenesis. Cell Div 4, 4 (2009).

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  • Mitotic Checkpoint
  • Thymoquinone
  • Centrosome Amplification
  • Scytonemin
  • Mitotic Progression