High consumption of fat, especially red meat, is a risk factor for cancer. Arachidonic acid and its precursor, linoleic acid, are major components in animal fats. Cellular metabolism of arachidonic acid by enzymes such as cyclooxygenase (COX) and lipoxygenase (LOX) generate a group of lipids, termed eicosanoids, which have potent and diverse biological activities. The eicosanoid product of 12-Lipoxygenase (12-LOX), 12(S)-hydroxyeicosatetraenoic acid [12(S)-HETE], modulates tumor growth and metastasis. In the previous funding period of this grant, we characterized the expression of 12-LOX in various tumors and further elucidated its role in tumor progression. We also identified a novel protein network, comprised of beta4 integrin, lamin A, cytokeratin 5, and phosphoprotein C8FW, which interacts with 12-LOX. When paired with alpha6, beta4 integrin subunit forms a major receptor for laminin. The alpha6beta4 integrin plays a major role in hemidesmosome, an adhesion complex that anchors epithelial cells to basement membrane. Mobilization of alpha6beta4 integrin from hemidesmosomes or elevated surface expression of alpha6beta4 has been implicated in malignant progression of various carcinomas. In this proposal, we will study further our novel observation regarding interaction between 12-LOX and beta4 integrin in the context of hemidesmosome formation and dissolution, cellular signaling, and tumor cell survival, invasion, and metastasis. The following specific aims are proposed: (1) Determine the structural basis for the interaction between beta4 integrin subunit and 12-LOX; (2) Study how alpha6beta4 regulates 12-LOX cellular localization and activity; (3) Determine whether 12-LOX regulates the function of alpha6beta4 in hemidesmosomes; (4) Study whether and how 12-LOX and beta4 integrin contribute to the survival of carcinoma cells; and (5) Determine whether and how 12-LOX and beta4 collaborate in carcinoma invasion in vitro and tumor progression in animal models. The proposed studies, when accomplished, will provide significant insights into eicosanoid regulation of tumor progression.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA029997-19
Application #
7126906
Study Section
Special Emphasis Panel (ZRG1-TME (01))
Program Officer
Woodhouse, Elizabeth
Project Start
1981-04-01
Project End
2009-03-31
Budget Start
2006-05-18
Budget End
2007-03-31
Support Year
19
Fiscal Year
2006
Total Cost
$331,767
Indirect Cost
Name
Wayne State University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
001962224
City
Detroit
State
MI
Country
United States
Zip Code
48202
Dilly, Ashok-Kumar; Tang, Keqin; Guo, Yande et al. (2017) Convergence of eicosanoid and integrin biology: Role of Src in 12-LOX activation. Exp Cell Res 351:1-10
Honn, Kenneth V; Guo, Yande; Cai, Yinlong et al. (2016) 12-HETER1/GPR31, a high-affinity 12(S)-hydroxyeicosatetraenoic acid receptor, is significantly up-regulated in prostate cancer and plays a critical role in prostate cancer progression. FASEB J 30:2360-9
Tang, Keqin; Cai, Yinlong; Joshi, Sangeeta et al. (2015) Convergence of eicosanoid and integrin biology: 12-lipoxygenase seeks a partner. Mol Cancer 14:111
Tucker, Stephanie C; Honn, Kenneth V (2013) Emerging targets in lipid-based therapy. Biochem Pharmacol 85:673-88
Dilly, Ashok-kumar; Ekambaram, Prasanna; Guo, Yande et al. (2013) Platelet-type 12-lipoxygenase induces MMP9 expression and cellular invasion via activation of PI3K/Akt/NF-?B. Int J Cancer 133:1784-91
Guo, Yande; Zhang, Wenliang; Giroux, Craig et al. (2011) Identification of the orphan G protein-coupled receptor GPR31 as a receptor for 12-(S)-hydroxyeicosatetraenoic acid. J Biol Chem 286:33832-40
Krishnamoorthy, Sriram; Jin, Rongxian; Cai, Yinlong et al. (2010) 12-Lipoxygenase and the regulation of hypoxia-inducible factor in prostate cancer cells. Exp Cell Res 316:1706-15
Tang, Yong; Wang, Man-Tzu; Chen, Yakun et al. (2009) Downregulation of vascular endothelial growth factor and induction of tumor dormancy by 15-lipoxygenase-2 in prostate cancer. Int J Cancer 124:1545-51
Tao, Xiao-hua; Shen, Jian-gen; Pan, Wei-li et al. (2008) Significance of SHP-1 and SHP-2 expression in human papillomavirus infected Condyloma acuminatum and cervical cancer. Pathol Oncol Res 14:365-71
Pidgeon, Graham P; Lysaght, Joanne; Krishnamoorthy, Sriram et al. (2007) Lipoxygenase metabolism: roles in tumor progression and survival. Cancer Metastasis Rev 26:503-24

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