Understanding of the mechanisms of melanocytic transformation is a continuing challenge. An in- depth knowledge of the genetic controls of cellular proliferation and cell division may provide critical information regarding the conversion of a normal melanocyte to its neoplastic phenotype. Polo-like kinases (Plks) are a family of highly conserved mitotic serine/threonine kinases that have been shown to play critical roles in cell division and cycle progression. Plk1 is the most widely studied member of the Plk family that contributes to multiple mitotic processes including the activation of the Cdk1/Cyclin B1 cascade, centrosome maturation, bipolar spindle formation and the regulation of Emi1 degradation at mitotic exit. Plk1 has been shown to be over-expressed in several cancers and a forced over-expression of Plk1 in normal cells has been found to cause a transformed phenotype and increased tumorigenicity. However, the functional role of Plk1 in melanocytic transformation is not well understood. In a recent study (J Invest Dermatol, In Press;Appendix-1), we have found that, i) Plk1 was over-expressed in both clinical tissue specimens and cultured human melanoma cells when compared to normal skin tissues and cultured normal melanocytes, respectively;and ii) genetic as well as chemical inhibition of Plk1 resulted in a significant decrease in the viability and growth of melanoma cells without affecting the normal human melanocytes. This study suggested that Plk1 may have an important role in melanoma survival and/or progression. However, additional studies are needed to determine the functional significance of Plk1 in melanocytic transformation and to define its molecular mechanism(s). In this study, we propose to challenge our novel hypothesis that Plk1 plays a critical role in melanocytic transformation and melanoma survival through modulation of Notch signaling. To test the hypothesis, the following specific aims are proposed: 1) To determine the expression pattern of Plk1, Notch and Numb during melanocytic transformation and melanoma development;2) To determine the involvement of Notch signaling as a downstream target of Plk1 in normal melanocytes and melanoma cells;3) To define the mechanism by which Plk1 regulates Notch1 signaling;and 4) To determine the functional and therapeutic significance of Plk1 in vivo in athymic nude mice xenografts. The outcome of proposed studies may define i) the role of Plk1 in melanocytic transformation and melanoma progression, ii) a novel connection between a key mitotic regulator (Plk1) with an important signaling pathway (Notch) involved in multiple cellular processes, including melanoma development.

Public Health Relevance

Understanding of the mechanisms of melanocytic transformation is a continuing challenge. An in depth knowledge of the genetic controls of cellular proliferation and cell division may provide critical information regarding the conversion of a normal melanocyte to its neoplastic phenotype. In this study, we will conduct pre-clinical studies to define the molecular mechanism of melanocytic transformation. Specifically, we will challenge our novel hypothesis that Plk1 plays a critical role in melanocytic transformation and melanoma survival through modulation of Notch signaling. The outcome of proposed studies may define i) the role of Plk1 in melanocytic transformation and melanoma progression, ii) a novel connection between a key mitotic regulator (Plk1) with an important signaling pathway (Notch) involved in multiple cellular processes, including melanoma development.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01AR059130-05
Application #
8685888
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Tseng, Hung H
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Dermatology
Type
Schools of Medicine
DUNS #
City
Madison
State
WI
Country
United States
Zip Code
53715
George, Jasmine; Ahmad, Nihal (2016) Mitochondrial Sirtuins in Cancer: Emerging Roles and Therapeutic Potential. Cancer Res 76:2500-6
Singh, Chandra K; Malas, Kareem M; Tydrick, Caitlin et al. (2016) Analysis of Zinc-Exporters Expression in Prostate Cancer. Sci Rep 6:36772
Singh, Chandra K; Nihal, Minakshi; Ahmad, Nihal (2016) Histone Deacetylase Inhibitory Approaches for the Management of Osteoarthritis. Am J Pathol 186:2555-8
Li, Jie; Wang, Ruixin; Schweickert, Patrick G et al. (2016) Plk1 inhibition enhances the efficacy of gemcitabine in human pancreatic cancer. Cell Cycle 15:711-9
Chen, Long; Ahmad, Nihal; Liu, Xiaoqi (2016) Combining p53 stabilizers with metformin induces synergistic apoptosis through regulation of energy metabolism in castration-resistant prostate cancer. Cell Cycle 15:840-9
Gutteridge, Rosie Elizabeth Ann; Ndiaye, Mary Ann; Liu, Xiaoqi et al. (2016) Plk1 Inhibitors in Cancer Therapy: From Laboratory to Clinics. Mol Cancer Ther 15:1427-35
George, Jasmine; Nihal, Minakshi; Singh, Chandra K et al. (2016) Pro-Proliferative Function of Mitochondrial Sirtuin Deacetylase SIRT3 in Human Melanoma. J Invest Dermatol 136:809-18
Chen, Long; Li, Jie; Farah, Elia et al. (2016) Cotargeting HSP90 and Its Client Proteins for Treatment of Prostate Cancer. Mol Cancer Ther 15:2107-18
Singh, Chandra K; Kaur, Satwinderjeet; George, Jasmine et al. (2015) Molecular signatures of sanguinarine in human pancreatic cancer cells: A large scale label-free comparative proteomics approach. Oncotarget 6:10335-48
Shao, Chen; Ahmad, Nihal; Hodges, Kurt et al. (2015) Inhibition of polo-like kinase 1 (Plk1) enhances the antineoplastic activity of metformin in prostate cancer. J Biol Chem 290:2024-33

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