Pancreatic cancer poses one of the greatest challenges in cancer research. Pancreatic adenocarcinoma is the fourth-leading cause of adult cancer mortality in the United States. The five-year survival rate remains at 1-3%, and the median survival duration after diagnosis is less than six months. Pancreatic cancer is characterized by locally advanced or metastatic disease and lack of response to current therapies. Based on the most frequently detected mutations in this disease, a genetic profile for pancreatic cancer is emerging. The expression of polo-like kinase 3 (Plk3), one of the four mammalian polo-like kinases, is significantly decreased in nearly 70% of human pancreatic cancer tissues and in most pancreatic cancer cell lines. Furthermore, Plk3 localizes to chromosome 1p32, a locus thought to contain cancer susceptibility genes. Recently, Plk3-knockout mice were generated and these mice developed tumors in various organs at advanced age. Plk3 is a multi-functional protein that plays critical roles in the regulation of apoptosis and responses to DNA damage. Expression of Plk3 induced apoptosis in pancreatic cancer cells in cell culture and inhibited pancreatic tumor growth by liposome- mediated gene transfer in a xenograft mouse model. These findings demonstrate that Plk3 functions as a tumor suppressor and plays an essential role in pancreatic cancer cell apoptosis. However, the underlying molecular mechanism through which Plk3 is regulated remains elusive. The long-term goal of our research is to develop more effective therapies for patients with pancreatic cancer. On the basis of our preliminary results, we hypothesize that loss of Plk3 expression plays an essential role in the development of pancreatic cancer and that Plk3 activation is an essential regulation that integrates signals that control genomic instability through inducible phosphorylation and/or interaction with adaptor molecules. To test our hypotheses, three specific aims were proposed: (1) demonstrate the role of Plk3 in the development of pancreatic cancer;(2) determine the expression of Plk3 is silenced in pancreatic cancer and role of Plk3 in the control of cell division and DNA damage checkpoints;(3) identify the mechanisms by which activation of Plk3 is regulated. The findings from our proposed study will provide insight into the mechanisms of Plk3 regulation and the essential role of Plk3 as a tumor suppressor in pancreatic cancer. Importantly, this study may discover novel molecular targets that could lead to more effective treatments for pancreatic cancer.
This project is aimed at elucidating the tumor suppressor function of Plk3 in pancreatic tumor development and determining the novel mechanism by which Plk3 is silenced and regulated. We hypothesize that down regulation of Plk3 plays an essential role in development of pancreatic cancer and activation of Plk3 by proleolytic cleavage is regulated by PI3K. We will test our hypothesis by three specific aims using a combination of Plk3 knockout mouse models and Plk3 knockdown cell lines with biochemical and cell biological approaches, to fill in the gaps in our understanding of the novel molecular mechanisms of Plk3 regulation and role of Plk3 in tumorigenesis of pancreas.
|Chang, Zhe; Li, Zhongkui; Wang, Xiaoyang et al. (2013) Deciphering the mechanisms of tumorigenesis in human pancreatic ductal epithelial cells. Clin Cancer Res 19:549-59|
|Carbone, Carmine; Moccia, Tania; Zhu, Cihui et al. (2011) Anti-VEGF treatment-resistant pancreatic cancers secrete proinflammatory factors that contribute to malignant progression by inducing an EMT cell phenotype. Clin Cancer Res 17:5822-32|