Recently a progression model for human pancreatic adenocarcinoma has been proposed based on the specific mutations identified in progressively more pathologic-appearing pancreatic ductal lesions termed pancreatic intraepithelial neoplasias. We seek to elucidate the underlying molecular mechanism that these genetic alterations play in initiating and maintaining tumorigenic phenotypes in normal pancreatic ductal epithelial cells, and invasive, angiogenic and metastatic phenotypes in human pancreatic adenocarcinoma. We have reported the first evidence that NF-kappaB, is constitutively activated in approximately 67% (16 of 24) of human pancreatic adenocarcinoma and 9 of 11 human pancreatic cancer cell lines, but not in normal pancreatic tissues or in immortalized/nontumorigenic pancreatic epithelial cells. Our ongoing study suggests that NF-kappaB activity in pancreatic cancer is associated with the occurrence of metastasis. We have shown that inhibition of constitutive RelA activity by a mutant IkappaBalpha (S32, 36A) suppressed liver metastasis of pancreas cancer cells in an orthotopic nude mouse model, suggesting that the constitutive RelA activity plays a key role in pancreas cancer metastasis. We identified several RelA downstream target genes relevant to pancreatic adenocarcinoma metastasis such as urokinase plasminogen activator (uPA), VEGF and bcl-xl. Analysis of genetically altered mouse embryonic fibroblasts reveals a novel finding that MAP3K signaling cascades activate IkappaB kinase (IKK) and NF-kappaB in response to growth factor and cytokine. However, the mechanism by which NF-kappaB is constitutively activated in pancreatic cancer still remains to be elucidated. In this study, we will test the hypothesis that the overexpression of EGF receptor and autocrine of lnterleukin-1alpha (IL-1alpha) induce constitutive RelA/NF-kappaB activation in pancreatic cancer cells and EGF and IL-alpha mediated RAS/MAPK signaling cascades for regulating IKK and NF-kappaB activity. These studies will determine how NF-kappaB is activated in response to EGF and IL-1alpha in the progression of human pancreatic adenocarcinoma. Our finding will provide a better understanding of the specific genetic alterations required in concert to induce metastatic phenotype in pancreatic cancer and the molecular basis for the design and development of potential therapeutic strategies for this disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA097159-03
Application #
6947852
Study Section
Metabolic Pathology Study Section (MEP)
Program Officer
Blair, Donald G
Project Start
2003-09-19
Project End
2007-08-31
Budget Start
2005-09-01
Budget End
2006-08-31
Support Year
3
Fiscal Year
2005
Total Cost
$215,175
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Internal Medicine/Medicine
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Zhuang, Zhuonan; Li, Hao; Lee, Harold et al. (2017) NEMO peptide inhibits the growth of pancreatic ductal adenocarcinoma by blocking NF-?B activation. Cancer Lett 411:44-56
Chiao, Paul J; Ling, Jianhua; Fu, Jie et al. (2017) Inhibition of Pancreatic Cancer by RhIL1RA-Response. Clin Cancer Res 23:3224
Ju, Huai-Qiang; Ying, Haoqiang; Tian, Tian et al. (2017) Mutant Kras- and p16-regulated NOX4 activation overcomes metabolic checkpoints in development of pancreatic ductal adenocarcinoma. Nat Commun 8:14437
Zhuang, Zhuonan; Ju, Huai-Qiang; Aguilar, Mitzi et al. (2016) IL1 Receptor Antagonist Inhibits Pancreatic Cancer Growth by Abrogating NF-?B Activation. Clin Cancer Res 22:1432-44
Ju, Huai-Qiang; Gocho, Takeshi; Aguilar, Mitzi et al. (2015) Mechanisms of Overcoming Intrinsic Resistance to Gemcitabine in Pancreatic Ductal Adenocarcinoma through the Redox Modulation. Mol Cancer Ther 14:788-98
Chang, Zhe; Ju, Huaiqiang; Ling, Jianhua et al. (2014) Cooperativity of oncogenic K-ras and downregulated p16/INK4A in human pancreatic tumorigenesis. PLoS One 9:e101452
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
Hu, Yumin; Lu, Weiqin; Chen, Gang et al. (2012) K-ras(G12V) transformation leads to mitochondrial dysfunction and a metabolic switch from oxidative phosphorylation to glycolysis. Cell Res 22:399-412
Ling, Jianhua; Kang, Ya'an; Zhao, Ruiying et al. (2012) KrasG12D-induced IKK2/?/NF-?B activation by IL-1? and p62 feedforward loops is required for development of pancreatic ductal adenocarcinoma. Cancer Cell 21:105-20
Melisi, Davide; Xia, Qianghua; Paradiso, Genni et al. (2011) Modulation of pancreatic cancer chemoresistance by inhibition of TAK1. J Natl Cancer Inst 103:1190-204

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