The long-term objective of this proposal is to obtain a better understanding of the molecular mechanisms governing the first step in tumor cell dissemination, namely motility. To accomplish this we propose to define the structural-functional relationship and mechanism of action of an autocrine motility factor (AMF) and its receptor (AMFR). We found AMF to be a phosphoglucose isomerase (PGI); a glycolytic enzyme that functions as an extracellular cytokine (AMF/neuroleukin/maturation factor). The AMFR is a unique member of the seven-transmembrane domain G-protein-coupled receptors (CXC2CR-1), AMF/PGI contains the CXXC thioredoxin-box motif which resembles the CC and CXC motifs of chemokines. AMF/PGI signaling pathway is similar to that of the chemokines and involves cytoskeletal rearrangement and morphological alteration mediated by small RhoA-like GTPases. We show here (Progress Report) that AMF/PGI is a hypoxic inducible gene, which in turn upregulates the expression of vascular endothelial growth factor (VEGF) and its receptor in endothelial cells and affects cellular oncogenic phenotype. Thus, we hypothesize that there is a cross-talk among hypoxia, glycolysis and angiogenesis and that AMF/PGI is a key molecule regulating, in part, tumor growth, angiogenesis, cell motility, invasion and metastasis. In addition, we have crystallized the human AMF/PGI and have provided the first structural evidence to the dichotomy between the isomerase and the cytokine activities of the molecule and provides evidence that its secretion is regulated by post-translation modification Based on the above and the data outlined in the Progress Report we set the following Specific Aims for this renewal application: 1) To establish the structural-functional relationship of AMF/PGI activity, 2) To study the regulation of AMF/PGI expression under hypoxia and 3) To determine the role of AMFIPGI in angiogenesis. It is expected that the accomplishment of these aims will help in understanding how and which of its structural motif(s) regulates its cytokine activity, how the signaling loop of AMF/PGI is transduced via AMFR, and to unveil its molecular role during hypoxia and angiogenesis. It is expected that the information obtained from this proposal will be utilized for therapeutic interventions to slow or eliminate invasion of cancer cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA051714-16
Application #
7006684
Study Section
Special Emphasis Panel (ZRG1-CPA (03))
Program Officer
Mohla, Suresh
Project Start
1991-08-01
Project End
2009-01-31
Budget Start
2006-02-01
Budget End
2007-01-31
Support Year
16
Fiscal Year
2006
Total Cost
$331,767
Indirect Cost
Name
Wayne State University
Department
Pathology
Type
Schools of Medicine
DUNS #
001962224
City
Detroit
State
MI
Country
United States
Zip Code
48202
Kho, Dhong Hyo; Zhang, Tianpeng; Balan, Vitaly et al. (2014) Autocrine motility factor modulates EGF-mediated invasion signaling. Cancer Res 74:2229-37
Wang, Ying; Ha, Seung-Wook; Zhang, Tianpeng et al. (2014) Polyubiquitylation of AMF requires cooperation between the gp78 and TRIM25 ubiquitin ligases. Oncotarget 5:2044-51
Kho, Dhong Hyo; Nangia-Makker, Pratima; Balan, Vitaly et al. (2013) Autocrine motility factor promotes HER2 cleavage and signaling in breast cancer cells. Cancer Res 73:1411-9
Ahmad, Aamir; Ali, Shadan; Ahmed, Alia et al. (2013) 3, 3'-Diindolylmethane enhances the effectiveness of herceptin against HER-2/neu-expressing breast cancer cells. PLoS One 8:e54657
Yanagawa, Takashi; Shinozaki, Tetsuya; Watanabe, Hideomi et al. (2012) Vascular endothelial growth factor-D is a key molecule that enhances lymphatic metastasis of soft tissue sarcomas. Exp Cell Res 318:800-8
Ahmad, Aamir; Aboukameel, Amro; Kong, Dejuan et al. (2011) Phosphoglucose isomerase/autocrine motility factor mediates epithelial-mesenchymal transition regulated by miR-200 in breast cancer cells. Cancer Res 71:3400-9
Niinaka, Yasufumi; Harada, Kiyoshi; Fujimuro, Masahiro et al. (2010) Silencing of autocrine motility factor induces mesenchymal-to-epithelial transition and suppression of osteosarcoma pulmonary metastasis. Cancer Res 70:9483-93
Araki, Kenichiro; Shimura, Tatsuo; Yajima, Toshiki et al. (2009) Phosphoglucose isomerase/autocrine motility factor promotes melanoma cell migration through ERK activation dependent on autocrine production of interleukin-8. J Biol Chem 284:32305-11
Funasaka, Tatsuyoshi; Hogan, Victor; Raz, Avraham (2009) Phosphoglucose isomerase/autocrine motility factor mediates epithelial and mesenchymal phenotype conversions in breast cancer. Cancer Res 69:5349-56
Funasaka, Tatsuyoshi; Hu, Huankai; Hogan, Victor et al. (2007) Down-regulation of phosphoglucose isomerase/autocrine motility factor expression sensitizes human fibrosarcoma cells to oxidative stress leading to cellular senescence. J Biol Chem 282:36362-9

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