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The Role of Polo-Like Kinase 1 in Carcinogenesis: Cause Or Consequence?

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The Role of Polo-Like Kinase 1 in Carcinogenesis: Cause Or Consequence? Published OnlineFirst November 21, 2013; DOI: 10.1158/0008-5472.CAN-13-2197 Cancer Review Research The Role of Polo-like Kinase 1 in Carcinogenesis: Cause or Consequence? Brian D. Cholewa1,2, Xiaoqi Liu4, and Nihal Ahmad1,2,3 Abstract Polo-like kinase 1 (Plk1) is a well-established mitotic regulator with a diverse range of biologic functions continually being identified throughout the cell cycle. Preclinical evidence suggests that the molecular targeting of Plk1 could be an effective therapeutic strategy in a wide range of cancers; however, that success has yet to be translated to the clinical level. The lack of clinical success has raised the question of whether there is a true oncogenic addiction to Plk1 or if its overexpression in tumors is solely an artifact of increased cellular proliferation. In this review, we address the role of Plk1 in carcinogenesis by discussing the cell cycle and DNA damage response with respect to their associations with classic oncogenic and tumor suppressor pathways that contribute to the transcriptional regulation of Plk1. A thorough examination of the available literature suggests that Plk1 activity can be dysregulated through key transformative pathways, including both p53 and pRb. On the basis of the available literature, it may be somewhat premature to draw a definitive conclusion on the role of Plk1 in carcinogenesis. However, evidence supports the notion that oncogene dependence on Plk1 is not a late occurrence in carcinogenesis and it is likely that Plk1 plays an active role in carcinogenic transformation. Cancer Res; 73(23); 1–8. Ó2013 AACR. Introduction of directly contributing to carcinogenesis. However, it is not Over the past two decades, since the advent of mammalian clear how and when Plk1 overexpression occurs during fi tumor formation. The answer to this critical question most polo-like kinase 1 (Plk1), the scienti c community has wit- 0 nessed a tremendous surge of studies aimed at defining the likely lies within one or more of Plk1 smanyregulatoryloops fi biologic functions of this mitotic kinase. We now have a wealth or protein interactions that have been identi ed in multiple b of information available about the spectacular role of Plk1 in oncogenes, including Akt, Myc, Mdm2, and -catenin, and – mitosis and throughout the cell cycle. However, the role of Plk1 tumor suppressors, such as p53, pRb, Brca2, and Pten (4 11). and its functional significance in carcinogenesis and tumor In fact, a recent review of the cancer genome by Vogelstein progression are not well understood. The question has been and colleagues categorized twelve signaling pathways that raised whether the consistently observed overexpression of regulate three core cellular processes, and an understanding Plk1 in a variety of cancers is due to its direct involvement in of these processes is among the most pressing needs in basic the neoplastic transformation of cells or if it is solely the result cancer research. Moreover, Plk1 has direct interaction with of increased proliferation due to the transformative process. all core processes and 75% of the signaling pathways (Fig. 1; Plk1 expression is cell cycle dependent, with a peak in mitosis, ref. 12). Furthermore, current evidence suggests that the which is evident in mitotically active normal tissues, and the dysregulation of Plk1 occurs early in carcinogenesis, as lack of chromosomal translocations or mutations found in the observed in hepato-, papillary, and pancreatic carcinomas – Plk1 gene supports the latter possibility (1, 2). On the other (13 15). In this review, we are attempting to highlight hand, it has been shown that forced overexpression of Plk1 components of transcriptional regulation and the resulting results in a malignant transformation of normal human fibro- overexpression of Plk1 in the context of classical oncogenic blasts in vitro that are capable of producing tumors when models involving the cell cycle and tumor suppressors p53 xenografted into nude mice (3), suggesting that Plk1 is capable and pRb to illustrate how the dysregulation of these path- ways may contribute to early events in carcinogenesis. Authors' Affiliations: 1Department of Dermatology; 2Molecular and Envi- Polo-like kinase 1: a controller of mitotic orchestra and ronmental Toxicology Center, University of Wisconsin; 3William S. Mid- beyond dleton Memorial VA Hospital, Madison, Wisconsin; and 4Department of Drosophila Biochemistry, Purdue University, West Lafayette, Indiana The discovery of the polo kinase in was made by Sunkel and Glover in 1988, following the observation that Corresponding Author: Nihal Ahmad, University of Wisconsin, B-25 Medical Science Center, 1300 University Avenue, Madison, WI 53706. mutant polo results in abnormal spindle formation (16). In Phone: 608-263-5359; Fax: 608-263-2919/5223; E-mail: 1993, Clay and colleagues determined the nucleotide sequence [email protected] of a cDNA encoding the mammalian protein kinase that was doi: 10.1158/0008-5472.CAN-13-2197 closely related to the enzyme encoded by the Drosophila Ó2013 American Association for Cancer Research. mutant polo and designated it as Plk (17). Today, the www.aacrjournals.org OF1 Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 2013 American Association for Cancer Research. Published OnlineFirst November 21, 2013; DOI: 10.1158/0008-5472.CAN-13-2197 Cholewa et al. AB Mdm2 G eno ma m inte ic DNA damage DN na A d nc am e control I3K c a P ont g rol e p53, Pten Br p53 t, ca k p21, 2, / A C , h e n k A l s i 2 β c i m - P GTSE1 Topors y s s C 2 C l o o a c t , m A h b t a l d x e l p p R v e i n i o o M n p e i , n v C p l c , r a c y u p16 p21 PIk1 FoxM1 u N M s PIk1 l l N e u 3 N C t m C a o t e b T t S l Cyclin D Cyclin E Cyclin B c l A h Cdc25c f T a Cdk4/6 Cdk2 Cdk1 S E t 8 2 e 3 F p , , F 2 k o x M M 1 Wee1 r e T g u r l a a t n i K Myt1 o n s P c A G2/M r RB E2F i M p t i o n a G1/S l p18 p19 © 2013 American Association for Cancer Research Figure 1. Plk1-interacting pathways. Plk1 overexpression and the resulting contribution to aberrant DNA damage control and genomic instability are accentuated by multiple feedback loops highlighting the interaction of Plk1 with several pathways involved in cell-cycle progression and the DNA damage response (A); and eight of 12 signaling pathways (middle ring) and all three core cellular processes (outer ring) identified by Vogelstein and colleagues (12) to confer a selective growth advantage in cancer (B). Plk1 has a direct interaction with a wide range of proteins (inner ring) that are transcribed by oncogenic (green) or tumor-suppressive (red) driver genes. Furthermore, Plk1 directly interacts with several proteins that are integral to the described pathways (orange; refs. 4–12, 32, 70, 72, 99–104). mammalian homolog family of Plks consists of five described thyroid, colon, prostate, pancreatic, head and neck, non–small members, Plk1–5, which are characterized by the presence of cell lung cancer, and non-Hodgkin lymphomas (35–43). an N-terminal kinase and C-terminal polo-box domain (17, 18). The Plk family is a group of highly conserved serine/threonine The cell cycle: filling in the gaps kinases that is typically associated with cell-cycle progression The cell cycle is a highly orchestrated progression of and mitosis; however, recent studies have suggested involve- events that culminates in cellular division and the produc- ment of this kinase family in cancer (reviewed in ref. 19). Plk1 tion of two daughter cells. Progression through each of the has emerged as a key mitotic regulator and is most commonly four main phases, G1 (Gap 1), S (Synthesis), G2 (Gap 2), and known for being a critical component of centrosome matura- M (mitosis), is tightly regulated through phosphorylation tion, kinetochore–microtubule attachment, bipolar spindle and ubiquitination events primarily driven by the "master formation, and cytokinesis (20–23). However, studies have cell-cycle regulators," cyclins, and cyclin-dependent kinases revealed a diverse range of biologic functions beyond typical (cdk). Plk1 expression is directly associated with the pro- mitotic events, including Plk10s involvement with p27 and gression of these phases, where it begins to accumulate RhoA, regulatory loops with the transcription factors FoxM1 during the S-phase, peaks at the G2–M transition, plateaus and Stat3, extensive interplay with Cdk1, phosphorylation throughout mitosis, and has a sharp reduction upon mitotic of p53 family members p63 and p73, as well as a recent exit (1). Of note, the expression of Plk1 in cancer cells differs implication in DNA replication (24–32). Furthermore, the from that of nontransformed cells in that it localizes to the overexpression of Plk1 has been linked to poor disease prog- nucleus before G2–M and can be easily detected even in the nosis and a decreased survival rate, whereas the inhibition of G1–S phase, suggesting that Plk1 must have cancer cell– Plk1 activity has emerged as a promising therapeutic target for specific functions in the interphase. This notion is supported cancer management in the clinical setting (33, 34). The exact by the observation that Plk1 is indeed involved in the G1–S role of Plk1 in carcinogenesis has yet to be determined; transition and DNA replication in cancer cells (44–46). The however, preclinical evidence suggests that Plk1 expression nuclear localization of Plk1 during the interphase of cancer may be necessary for cancer cell survival and is overexpressed cells has been neglected for a long time in the field as one in a variety of cancers, including melanoma, breast, ovarian, tends to focus on its classical mitotic functions, but this OF2 Cancer Res; 73(23) December 1, 2013 Cancer Research Downloaded from cancerres.aacrjournals.org on September 25, 2021.
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