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 structure-functional relationship and mechanism of action of an autocrine motility factor (AMF) and its receptor (AMFR/gp78). Phosphoglucose isomerase (PGI) is a ubiquitous housekeeping cytosolic enzyme that plays a key role in both glycolysis and gluconeogenesis pathways. Upon secretion PGI acts as a potent mitogen/cytokine e.g. tumor autocrine motility factor (AMF), neuroleukin (NLK), and maturation factor (MF), sperm antigen-36 and myofibril-bound serine proteinase inhibitor and therefore represents a prototype for multifunction proteins i.e. "moonlighting proteins". AMF/PGI contains the CXXC thioredoxin-box motif which resembles the CC and CXC motifs of chemokines and its signaling pathway involves cytoskeletal rearrangement and morphological alteration. We show here that AMF/PGI is a hypoxic inducible gene, which in turn up-regulates the expression of vascular endothelial growth factor (VEGF) and its receptor in endothelial cells and affects cellular oncogenic phenotype. AMFR, a 78 kDa seven-transmembrane glycoprotein is an orphan chemokine receptor, (gp78/AMFR/CXC2CR-1) that performs an additional function in the endoplasmic reticulum (ER) with an intrinsic RING finger-dependent ubiquitin protein ligase (E3) activity. Overexpression of AMF/AMFR has been found in a wide spectrum of malignancies, and regulates migration-dependent processes during invasion and metastasis in association with epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET). In addition, we provided evidence that down-regulation of AMF/PGI expression results in loss of tumorigenicity leading to cell senescence. Thus, we hypothesize that there is cross-talk among glycolysis, hypoxia, cell growth and motility and that AMF/AMFR autocrine loop regulates, in part, tumor cell invasion and metastasis. Based on the above and the data outlined in the Progress Report we set the following Specific Aims for this renewal application: 1) To define the domains and mechanisms involved in AMF/AMFR regulated tumorigenicity and cell motility 2) To study the role of gp78/AMFR ubiquitin ligase in AMF ubiquitination and 3) To establish the role of AMF/AMFR in EMT'MET transitions. Central to targeting AMF/AMFR system and the relevance of this proposal to cancer biology will be the dissociation between cytokine and glycolytic activities as well as between the cell surface receptor and the intracellular ligase functions. This represents a major challenge of this proposal as it could bring about the development of specific small inhibitor molecules able to differentially inhibit a particular function without disturbing the other one and highlights its significance and novelty and would lead to a scientific evolution associated with cancer progression with the hope that these studies will result in better diagnosis, treatment and development of rational therapy.

Public Health Relevance

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 structure-functional relationship and mechanism of action of an autocrine motility factor (AMF) and its receptor (AMFR/gp78). It is expected that these studies will lead to a better diagnosis, treatment and development of rational therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA051714-22
Application #
8265659
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Woodhouse, Elizabeth
Project Start
1991-08-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
22
Fiscal Year
2012
Total Cost
$323,988
Indirect Cost
$110,838
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
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
Yanagawa, Takashi; Funasaka, Tatsuyoshi; Tsutsumi, Soichi et al. (2007) Regulation of phosphoglucose isomerase/autocrine motility factor activities by the poly(ADP-ribose) polymerase family-14. Cancer Res 67:8682-9

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