G-protein coupled receptors (GPCRs) and signal transduction pathways represent important specific targets for a variety of human diseases, ranging from the control of blood pressure, allergic response, hormonal disorders, to human cancer. We have recently identified a subfamily of prostate-specific G-protein coupled receptors (PSGRs). Although these specific receptors shares sequence homology with olfactory GPCRs in their seven putative transmembrane domains, the expression of PSGRs is highly restricted to the human prostate gland and is increased dramatically in human prostate cancers compared to matched normal tissues. Aberrant expression of PSGRs correlates well with prostate tumorigenesis, suggesting important roles of PSGRs in prostate cancer development and progression. However, how these prostate specific G-protein coupled receptors regulate prostate tumor progression is still not clear, and the signaling pathways and genes/proteins regulated by PSGRs have not been identified and characterized. Therefore, our long-term objectives are to understand the functions and signaling pathways of these PSGRs;and to determine whether PSGRs can be used as biomarkers in diagnosis and as molecular targets in the treatment of prostate cancers. We will test the hypothesis that overexpression of PSGRs will lead to the activation of specific growth signaling pathways to promote prostate tumor development and progression.
Three specific aims are proposed in this grant application: 1) Determine the direct correlations of PSGR overexpression with prostate cancer development using orthotopic and transgenic mouse models;2) Delineate the mechanism of action for prostate-specific G-protein coupled receptors in prostate cancer development and progression;3) Determine the cooperative functions of PSGR overexpression and the loss of PTEN tumor suppressor gene in prostate tumor progression and metastasis. Results obtained from this study will provide information on the physiological functions of these prostate-specific G-protein coupled receptors in cancer development and progression and their potential uses as molecular targets in prostate cancer therapy.
The prostate-specific G-protein coupled receptors (PSGRs) are a novel subfamily of specific receptors identified in our lab and are dramatically increased in prostate cancer. Overexpression of PSGRs promotes cancer cell proliferation and tumorigenesis. Our long term goals are to understand how these prostate-specific receptors and their signaling pathways regulate prostate cancer development and progression;and to determine whether PSGRs can be used as biomarkers and molecular targets in the diagnosis and treatment of prostate cancers.
|Rodriguez, M; Siwko, S; Zeng, L et al. (2016) Prostate-specific G-protein-coupled receptor collaborates with loss of PTEN to promote prostate cancer progression. Oncogene 35:1153-62|
|Yi, Tingfang; Weng, Jinsheng; Siwko, Stefan et al. (2014) LGR4/GPR48 inactivation leads to aniridia-genitourinary anomalies-mental retardation syndrome defects. J Biol Chem 289:8767-80|
|Du, Bing; Luo, Weijia; Li, Ruimei et al. (2013) Lgr4/Gpr48 negatively regulates TLR2/4-associated pattern recognition and innate immunity by targeting CD14 expression. J Biol Chem 288:15131-41|
|Wang, Ying; Dong, Jie; Li, Dali et al. (2013) Lgr4 regulates mammary gland development and stem cell activity through the pluripotency transcription factor Sox2. Stem Cells 31:1921-31|
|Luo, Weijia; Rodriguez, Melissa; Valdez, Joseph M et al. (2013) Lgr4 is a key regulator of prostate development and prostate stem cell differentiation. Stem Cells 31:2492-505|
|Wang, Y; Chen, Y; Wang, J et al. (2012) Xanthohumol, a prenylated chalcone derived from hops, suppresses cancer cell invasion through inhibiting the expression of CXCR4 chemokine receptor. Curr Mol Med 12:153-62|
|Chen, Jing; Wang, Jieqiong; Lin, Lei et al. (2012) Inhibition of STAT3 signaling pathway by nitidine chloride suppressed the angiogenesis and growth of human gastric cancer. Mol Cancer Ther 11:277-87|
|Tang, Xiao-long; Wang, Ying; Li, Da-li et al. (2012) Orphan G protein-coupled receptors (GPCRs): biological functions and potential drug targets. Acta Pharmacol Sin 33:363-71|
|Pang, Xiufeng; Wu, Yuanyuan; Wu, Yougen et al. (2011) (-)-Gossypol suppresses the growth of human prostate cancer xenografts via modulating VEGF signaling-mediated angiogenesis. Mol Cancer Ther 10:795-805|
|Cho, Sung-Gook; Wang, Ying; Rodriguez, Melissa et al. (2011) Haploinsufficiency in the prometastasis Kiss1 receptor Gpr54 delays breast tumor initiation, progression, and lung metastasis. Cancer Res 71:6535-46|
Showing the most recent 10 out of 11 publications