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Department of Dermatology, University of Wisconsin Comprehensive Cancer Center, Molecular and Environmental Toxicology Center, University of Wisconsin, Madison, Wisconsin, USA
1Correspondence: Department of Dermatology, University of Wisconsin, Medical Science Center, 1300 University Ave., Madison, WI 53706, USA. E-mail: nahmad{at}wisc.edu
ABSTRACT
Second only to skin cancer, cancer of the prostate gland (CaP) is the most commonly occurring cancer in American men. Existing treatment approaches and surgical intervention have been unable to effectively manage this dreaded cancer; therefore, efforts are ongoing to explore novel targets and strategies for the management of CaP. A complete understanding of the genetic control of the processes of cellular proliferation and programmed cell death, or "apoptosis," may provide the basis for the rational design of novel therapeutic strategies against CaP. Key regulators for the mitotic progression in mammalian cells are the polo-like kinases (Plks). The activity of Plk1 is elevated in tissues and cells with a high mitotic index, including cancer cells. An increasing body of evidence suggests that the level of Plk1 expression has prognostic value for predicting outcomes in patients with some cancers such as lung cancer, squamous cell carcinomas of the head and neck, melanomas, and ovarian and endometrial carcinomas. However, the role of Plk1 in CaP is not known. Here, a hypothesis is put forward that Plk 1 plays a critical role in the development of prostate cancer; and the silencing of Plk1 will result in elimination of human CaP cells via an inactivation of cyclin-dependent kinase 1 (Cdc2)/cyclin B 1-mediated mitotic arrest followed by apoptosis. A corollary to this hypothesis is that Plk1 could serve as a target for the intervention of CaP in humans. Therefore, if the hypothesis is tested to be true, it is conceivable that gene therapeutic approaches aimed at Plk1 or the pharmacological inhibitors of Plk1 may be developed for the treatment/management of CaP.—Ahmad, N. Polo-like kinase (Plk) 1: a novel target for the treatment of prostate cancer.
Key Words: Plk inhibitor • gene therapy • apoptosis • cell cycle
WHY THE PROBLEM OF PROSTATE CANCER NEEDS AND URGENT ATTENTION
CANCER OF THE PROSTATE GLAND (CaP) is the second most commonly occurring cancer in American men. According to estimates from the American Cancer Society, in 2003 
220,900 new cases of CaP will have been diagnosed in the U.S., and 28,900 men will die of the disease (1)
. Although the overall incidence of CaP and its related mortality has decreased over the last decade, the incidence of this cancer in the elderly population (over 65 years) is still increasing (1)
. The existing treatment approaches and surgical intervention have not been able to effectively manage this dreaded cancer, and therefore there is an urgent need to explore novel targets and design novel strategies for its management.
WHY POLO-LIKE KINASES ARE IMPORTANT
A complete understanding of the genetic control of the processes of cellular proliferation and programmed cell death (viz., "apoptosis") may provide a basis for the rational design of novel therapeutic strategies against CaP. Key regulators of the mitotic progression in mammalian cells are the polo-like kinases (Plks). The activity of Plk1 is elevated in tissues and cells with a high mitotic index, including cancer cells. However, the role of Plk1 in CaP is not clear. The important functions/roles of Plk1 in physiological processes are discussed in the following pages.
Role of polo-like kinase in cellular proliferation
Events of the cell cycle, the stages at which the cell proliferates and divides, are facilitated and controlled by multiple signaling pathways. Among the many regulatory enzymes that contribute to these processes, the polo-like kinase is regarded to be critical. Plks have been reported to mediate multiple mitotic processes including bipolar spindle formation, activation of Cdc25C, actin ring formation, centrosome maturation, and activation of the anaphase-promoting complex. The activity of Plk1 is elevated in tissues and cells with a high mitotic index, including cancer cells (2
3
4
5
6
7
8)
. An increasing body of evidence suggests that the level of Plk1 expression has prognostic value for predicting outcomes in patients with several cancers, including non-small cell lung cancer, squamous cell carcinomas of the head and neck, melanomas, oropharyngeal carcinomas, and ovarian and endometrial carcinomas (2
3
4
5
6
7
8)
. The importance of Plk1 as a measure of tumor aggressiveness seems to come from its different functions during mitotic progression, particularly its role in the G2/M transition (phosphorylation of cyclin B1, a component of the mitosis-promoting factor) (2
, 4
5
6
7
8
9)
. Plk1 also phosphorylates substrates that are involved in several additional steps of mitotic progression, including components of the anaphase-promoting complex and components of the cytokinesis machinery (2
, 4
5
6
7
8
9)
.
Role of Plk1 in centrosome abnormalities
Lane and Nigg (10)
used a cell duplication microinjection assay to investigate the in vivo function of Plk1 in immortalized (HeLa) and nonimmortalized (Hs68) human cells. Injection of anti-Plk1 antibodies (Plk1+) at various stages of the cell cycle had no effect on the kinetics of DNA replication but was found to severely impair the ability of cells to divide. Analysis of Plk1(+)-injected, mitotically arrested HeLa cells by fluorescence microscopy revealed abnormal distributions of condensed chromatin and monoastral microtubule arrays that were nucleated from duplicated but unseparated centrosomes. The centrosomes in Plk1(+)-injected cells were found to be drastically reduced in size, and the accumulation of 
-tubulin and MPM-2 immunoreactivity was impaired. This study (10)
suggested that Plk1 is necessary for the functional maturation of centrosomes in late G2/early prophase and for the establishment of a bipolar spindle.
Spankuch-Schmitt et al. (9)
demonstrated that inhibition of Plk1 results in induction of apoptosis and spindle formation in some cancer cells. Centrosomes play a critical role in generating genetic instability in cancer cells (11
, 12)
. They contribute to spindle abnormalities and disturbed chromosome segregation, which are often accompanied by profound alterations in key cellular functions, including regulation of apoptosis, control of cell cycle progression and cell cycle checkpoints, and cell growth regulation. Recent observations have shown that centrosomal abnormalities can be detected in early forms of human prostate cancer (13)
. Extra centrosomes in cancer cells might lead to chromosome mis-sorting and damage, causing aneuploidy, which may induce the loss of tumor suppressor genes or activate oncogenes (9)
. Thus, it is possible that centrosomes are a driving force behind cancer formation, not a consequence of it (9)
. Therefore, it is important to study the effect of Plk1 on centrosome abnormalities in CaP.
Role of Plk1 in regulation of cell cycle and apoptosis
Checkpoint activation by DNA damage during G2 prevents activation of cyclin B/Cdc2 complexes by the Cdc25C phosphatase; as a consequence, mitotic entry is blocked (2
, 4
5
6
, 14)
. Inhibition of Cdc25C can be mediated by the DNA damage-activated kinases Chk1/Cds1, resulting in nuclear exclusion and direct inhibition of Cdc25C catalytic activity (2
, 4
5
6
, 14)
. In addition, Cdc25C activation requires positive regulatory phosphorylation, which can be established by cyclin B/Cdc2 complexes or by incubation with Plks (2
, 4
5
6
, 14)
. In fact, in Xenopus, depletion of the polo-like kinase Plk1 causes a block in Cdc25C activation, which suggests that Plks provide the initial trigger for Cdc25C activation (2
, 4
5
6
, 14)
. Several lines of evidence indicate that Cdc5, the polo-like kinase in budding yeast, is controlled by the DNA damage checkpoint (2
, 4
5
6
, 14)
. Plk1 activity normally appears at the onset of mitosis. Thus, Plk is a serine-threonine kinase that appears to function in mitotic control in mammalian cells (1
, 4
5
6
, 14)
. It has been demonstrated that Plk mRNA expression is low at the G1 
S transition, increases during S phase, and is maximally expressed during G2 M. Some evidence has also suggested the role of Plk in induction of apoptosis (9)
.
WHAT IS THE HYPOTHESIS?
Based on the above discussion, a hypothesis is proposed as follows:
Polo-like kinase (Plk) 1 plays a critical role in the development of prostate cancer; and the silencing of Plk1 will result in elimination of human CaP cells via an inactivation of cyclin-dependent kinase 1 (Cdc2)/cyclin B 1-mediated mitotic arrest followed by apoptosis. A corollary to this hypothesis is that Plk1 could serve as a target for the intervention of CaP in humans (Fig. 1
).
|
Thus, if the hypothesis is tested to be true, it is conceivable that gene therapeutic approaches aimed at Plk1 or the pharmacological inhibitors of Plk1 may be developed for the management of CaP.
ACKNOWLEDGMENTS
This paper is dedicated to my mentor, Hasan Mukhtar, for his help, support, and encouragement to further my career.
Received for publication August 27, 2003. Accepted for publication September 14, 2003.
REFERENCES
This article has been cited by other articles:
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  L. L. Garland, C. Taylor, D. L. Pilkington, J. L. Cohen, and D. D. Von Hoff A Phase I Pharmacokinetic Study of HMN-214, a Novel Oral Stilbene Derivative with Polo-Like Kinase-1-Interacting Properties, in Patients with Advanced Solid Tumors Clin. Cancer Res., September 1, 2006; 12(17): 5182 - 5189. [Abstract] [Full Text] [PDF]
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 B. Spankuch, S. Heim, E. Kurunci-Csacsko, C. Lindenau, J. Yuan, M. Kaufmann, and K. Strebhardt Down-regulation of Polo-like Kinase 1 Elevates Drug Sensitivity of Breast Cancer Cells In vitro and In vivo Cancer Res., June 1, 2006; 66(11): 5836 - 5846. [Abstract] [Full Text] [PDF]
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 A. Astrinidis, W. Senapedis, and E. P. Henske Hamartin, the tuberous sclerosis complex 1 gene product, interacts with polo-like kinase 1 in a phosphorylation-dependent manner Hum. Mol. Genet., January 15, 2006; 15(2): 287 - 297. [Abstract] [Full Text] [PDF]
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