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Erschienen in: Medical Oncology 3/2015

01.03.2015 | Original Paper

GPCR48/LGR4 promotes tumorigenesis of prostate cancer via PI3K/Akt signaling pathway

verfasst von: Fang Liang, Junmin Yue, Junyong Wang, Lijuan Zhang, Rui Fan, Hao Zhang, Qingsong Zhang

Erschienen in: Medical Oncology | Ausgabe 3/2015

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Abstract

G-protein-coupled receptor (GPCR) 48, also known as leucine-rich repeat-containing G-protein-coupled receptor (LGR) 4, is an orphan receptor belonging to the GPCR superfamily, which plays an important role in the development of various organs and multiple cancers. However, the function of GPCR48/LGR4 in prostate cancer has not been fully investigated. Herein, GPCR48/LGR4 was overexpressed and silenced in prostate cancer cells via plasmid and shRNA transfection, respectively. The expression of GPCR48/LGR4 in mRNA and protein levels was analyzed using RT-qPCR and Western blotting, respectively. Subsequently, we demonstrated the effects of GPCR48/LGR4 on the migration, invasion, proliferation and apoptosis of prostate cancer cells, including Du145 and PC-3 cells. Next, we investigated the relationship between GPCR48/LGR4 and phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/Akt signaling pathway. The results showed that the overexpression of GPCR48/LGR4 was associated with the up-regulation of Akt, a key effector of PI3K/Akt signaling pathway, which meantime up-regulated the expression of mammalian target of rapamycin (mTOR) and glycogen synthase kinase 3β (GSK-3β), while down-regulated forkhead box, class O (FOXO), all of whom are the downstream targets of PI3K/Akt signaling pathway. Hence, the results suggested that GPCR48/LGR4 may regulate prostate cancer cells and tumor growth via the PI3K/Akt signaling pathway and could provide a better therapeutic target for the diagnosis and treatment of prostate cancer.
Literatur
1.
Zurück zum Zitat Tenesa A, Dunlop MG. New insights into the aetiology of colorectal cancer from genome-wide association studies. Nat Rev Genet. 2009;10:353–8.CrossRefPubMed Tenesa A, Dunlop MG. New insights into the aetiology of colorectal cancer from genome-wide association studies. Nat Rev Genet. 2009;10:353–8.CrossRefPubMed
2.
Zurück zum Zitat Narita S, Tsuchiya N, Habuchi T. Treatment for high-risk localized prostate cancer. Nihon Rinsho. 2014;72:2212–6.PubMed Narita S, Tsuchiya N, Habuchi T. Treatment for high-risk localized prostate cancer. Nihon Rinsho. 2014;72:2212–6.PubMed
3.
Zurück zum Zitat Ghosh D, Yu H, Tan XF, Lim TK, Zubaidah RM, Tan HT, et al. Identification of key players for colorectal cancer metastasis by iTRAQ quantitative proteomics profiling of isogenic SW480 and SW620 cell lines. J Proteome Res. 2011;10:4373–87.CrossRefPubMed Ghosh D, Yu H, Tan XF, Lim TK, Zubaidah RM, Tan HT, et al. Identification of key players for colorectal cancer metastasis by iTRAQ quantitative proteomics profiling of isogenic SW480 and SW620 cell lines. J Proteome Res. 2011;10:4373–87.CrossRefPubMed
4.
Zurück zum Zitat O’Neill PR, Giri L, Karunarathne WK, Patel AK, Venkatesh KV, Gautam N. The structure of dynamic GPCR signaling networks. Wiley Interdiscip Rev Syst Biol Med. 2014;6:115–23.PubMedCentralCrossRefPubMed O’Neill PR, Giri L, Karunarathne WK, Patel AK, Venkatesh KV, Gautam N. The structure of dynamic GPCR signaling networks. Wiley Interdiscip Rev Syst Biol Med. 2014;6:115–23.PubMedCentralCrossRefPubMed
5.
Zurück zum Zitat Zhu YB, Xu L, Chen M, Ma HN, Lou F. GPR48 promotes multiple cancer cell proliferation via activation of Wnt signaling. Asian Pac J Cancer Prev. 2013;14:4775–8.CrossRefPubMed Zhu YB, Xu L, Chen M, Ma HN, Lou F. GPR48 promotes multiple cancer cell proliferation via activation of Wnt signaling. Asian Pac J Cancer Prev. 2013;14:4775–8.CrossRefPubMed
6.
Zurück zum Zitat Luo W, Rodriguez M, Valdez JM, Zhu X, Tan K, Li D, et al. Lgr4 is a key regulator of prostate development and prostate stem cell differentiation. Stem Cells. 2013;31:2492–505.PubMedCentralCrossRefPubMed Luo W, Rodriguez M, Valdez JM, Zhu X, Tan K, Li D, et al. Lgr4 is a key regulator of prostate development and prostate stem cell differentiation. Stem Cells. 2013;31:2492–505.PubMedCentralCrossRefPubMed
7.
Zurück zum Zitat Luo J, Zhou W, Zhou X, Li D, Weng J, Yi Z, et al. Regulation of bone formation and remodeling by G-protein-coupled receptor 48. Development. 2009;136:2747–56.PubMedCentralCrossRefPubMed Luo J, Zhou W, Zhou X, Li D, Weng J, Yi Z, et al. Regulation of bone formation and remodeling by G-protein-coupled receptor 48. Development. 2009;136:2747–56.PubMedCentralCrossRefPubMed
8.
Zurück zum Zitat Kudo M, Chen T, Nakabayashi K, Hsu SY, Hsueh AJ. The nematode leucine-rich repeat-containing, G protein-coupled receptor (LGR) protein homologous to vertebrate gonadotropin and thyrotropin receptors is constitutively active in mammalian cells. Mol Endocrinol. 2000;14:272–84.CrossRefPubMed Kudo M, Chen T, Nakabayashi K, Hsu SY, Hsueh AJ. The nematode leucine-rich repeat-containing, G protein-coupled receptor (LGR) protein homologous to vertebrate gonadotropin and thyrotropin receptors is constitutively active in mammalian cells. Mol Endocrinol. 2000;14:272–84.CrossRefPubMed
9.
Zurück zum Zitat Mendive F, Laurent P, Van Schoore G, Skarnes W, Pochet R, Vassart G. Defective postnatal development of the male reproductive tract in LGR4 knockout mice. Dev Biol. 2006;290:421–34.CrossRefPubMed Mendive F, Laurent P, Van Schoore G, Skarnes W, Pochet R, Vassart G. Defective postnatal development of the male reproductive tract in LGR4 knockout mice. Dev Biol. 2006;290:421–34.CrossRefPubMed
10.
Zurück zum Zitat Yamashita R, Takegawa Y, Sakumoto M, Nakahara M, Kawazu H, Hoshii T, et al. Defective development of the gall bladder and cystic duct in Lgr4-hypomorphic mice. Dev Dyn. 2009;238:993–1000.CrossRefPubMed Yamashita R, Takegawa Y, Sakumoto M, Nakahara M, Kawazu H, Hoshii T, et al. Defective development of the gall bladder and cystic duct in Lgr4-hypomorphic mice. Dev Dyn. 2009;238:993–1000.CrossRefPubMed
11.
Zurück zum Zitat Weng J, Luo J, Cheng X, Jin C, Zhou X, Qu J, et al. Deletion of G protein-coupled receptor 48 leads to ocular anterior segment dysgenesis (ASD) through down-regulation of Pitx2. Proc Natl Acad Sci USA. 2008;105:6081–6.PubMedCentralCrossRefPubMed Weng J, Luo J, Cheng X, Jin C, Zhou X, Qu J, et al. Deletion of G protein-coupled receptor 48 leads to ocular anterior segment dysgenesis (ASD) through down-regulation of Pitx2. Proc Natl Acad Sci USA. 2008;105:6081–6.PubMedCentralCrossRefPubMed
12.
Zurück zum Zitat Daaka Y. G proteins in cancer: the prostate cancer paradigm. Sci STKE. 2004;2004:re2. Daaka Y. G proteins in cancer: the prostate cancer paradigm. Sci STKE. 2004;2004:re2.
13.
Zurück zum Zitat Dorsam RT, Gutkind JS. G-protein-coupled receptors and cancer. Nat Rev Cancer. 2007;7:79–94.CrossRefPubMed Dorsam RT, Gutkind JS. G-protein-coupled receptors and cancer. Nat Rev Cancer. 2007;7:79–94.CrossRefPubMed
14.
15.
Zurück zum Zitat Harada M, Noguchi M, Itoh K. Target molecules in specific immunotherapy against prostate cancer. Int J Clin Oncol. 2003;8:193–9.CrossRefPubMed Harada M, Noguchi M, Itoh K. Target molecules in specific immunotherapy against prostate cancer. Int J Clin Oncol. 2003;8:193–9.CrossRefPubMed
16.
Zurück zum Zitat Wu J, Xie N, Xie K, Zeng J, Cheng L, Lei Y, et al. GPR48, a poor prognostic factor, promotes tumor metastasis and activates β-catenin/TCF signaling in colorectal cancer. Carcinogenesis. 2013;34:2861–9.CrossRefPubMed Wu J, Xie N, Xie K, Zeng J, Cheng L, Lei Y, et al. GPR48, a poor prognostic factor, promotes tumor metastasis and activates β-catenin/TCF signaling in colorectal cancer. Carcinogenesis. 2013;34:2861–9.CrossRefPubMed
17.
Zurück zum Zitat Hsu SY, Liang SG, Hsueh AJ. Characterization of two LGR genes homologous to gonadotropin and thyrotropin receptors with extracellular leucine-rich repeats and a G protein-coupled, seven-transmembrane region. Mol Endocrinol. 1998;12:1830–45.CrossRefPubMed Hsu SY, Liang SG, Hsueh AJ. Characterization of two LGR genes homologous to gonadotropin and thyrotropin receptors with extracellular leucine-rich repeats and a G protein-coupled, seven-transmembrane region. Mol Endocrinol. 1998;12:1830–45.CrossRefPubMed
18.
Zurück zum Zitat Fresno Vara JA, Casado E, de Castro J, Cejas P, Belda-Iniesta C, Gonzalez-Baron M. PI3K/Akt signalling pathway and cancer. Cancer Treat Rev. 2004;30:193–204.CrossRefPubMed Fresno Vara JA, Casado E, de Castro J, Cejas P, Belda-Iniesta C, Gonzalez-Baron M. PI3K/Akt signalling pathway and cancer. Cancer Treat Rev. 2004;30:193–204.CrossRefPubMed
19.
Zurück zum Zitat Kasbohm EA, Guo R, Yowell CW, Bagchi G, Kelly P, Arora P, et al. Androgen receptor activation by G(s) signaling in prostate cancer cells. J Biol Chem. 2005;280:11583–9.CrossRefPubMed Kasbohm EA, Guo R, Yowell CW, Bagchi G, Kelly P, Arora P, et al. Androgen receptor activation by G(s) signaling in prostate cancer cells. J Biol Chem. 2005;280:11583–9.CrossRefPubMed
20.
Zurück zum Zitat Dai J, Shen R, Sumitomo M, Stahl R, Navarro D, Gershengorn MC, et al. Synergistic activation of the androgen receptor by bombesin and low-dose androgen. Clin Cancer Res. 2002;8:2399–405.PubMed Dai J, Shen R, Sumitomo M, Stahl R, Navarro D, Gershengorn MC, et al. Synergistic activation of the androgen receptor by bombesin and low-dose androgen. Clin Cancer Res. 2002;8:2399–405.PubMed
21.
Zurück zum Zitat Lee LF, Guan J, Qiu Y, Kung HJ. Neuropeptide-induced androgen independence in prostate cancer cells: roles of nonreceptor tyrosine kinases Etk/Bmx, Src, and focal adhesion kinase. Mol Cell Biol. 2001;21:8385–97.PubMedCentralCrossRefPubMed Lee LF, Guan J, Qiu Y, Kung HJ. Neuropeptide-induced androgen independence in prostate cancer cells: roles of nonreceptor tyrosine kinases Etk/Bmx, Src, and focal adhesion kinase. Mol Cell Biol. 2001;21:8385–97.PubMedCentralCrossRefPubMed
22.
Zurück zum Zitat Xie Y, Wolff DW, Lin MF, Tu Y. Vasoactive intestinal peptide transactivates the androgen receptor through a protein kinase A-dependent extracellular signal-regulated kinase pathway in prostate cancer LNCaP cells. Mol Pharmacol. 2007;72:73–85.CrossRefPubMed Xie Y, Wolff DW, Lin MF, Tu Y. Vasoactive intestinal peptide transactivates the androgen receptor through a protein kinase A-dependent extracellular signal-regulated kinase pathway in prostate cancer LNCaP cells. Mol Pharmacol. 2007;72:73–85.CrossRefPubMed
23.
Zurück zum Zitat Nelson JB. Endothelin inhibition: novel therapy for prostate cancer. J Urol. 2003;170:S65–7 discussion S7–8.CrossRefPubMed Nelson JB. Endothelin inhibition: novel therapy for prostate cancer. J Urol. 2003;170:S65–7 discussion S7–8.CrossRefPubMed
24.
Zurück zum Zitat Growcott JW. Preclinical anticancer activity of the specific endothelin A receptor antagonist ZD4054. Anticancer Drugs. 2009;20:83–8.CrossRefPubMed Growcott JW. Preclinical anticancer activity of the specific endothelin A receptor antagonist ZD4054. Anticancer Drugs. 2009;20:83–8.CrossRefPubMed
25.
Zurück zum Zitat Takahashi H, Ishii H, Nishida N, Takemasa I, Mizushima T, Ikeda M, et al. Significance of Lgr5(+ve) cancer stem cells in the colon and rectum. Ann Surg Oncol. 2011;18:1166–74.CrossRefPubMed Takahashi H, Ishii H, Nishida N, Takemasa I, Mizushima T, Ikeda M, et al. Significance of Lgr5(+ve) cancer stem cells in the colon and rectum. Ann Surg Oncol. 2011;18:1166–74.CrossRefPubMed
26.
Zurück zum Zitat Fan XS, Wu HY, Yu HP, Zhou Q, Zhang YF, Huang Q. Expression of Lgr5 in human colorectal carcinogenesis and its potential correlation with β-catenin. Int J Colorectal Dis. 2010;25:583–90.CrossRefPubMed Fan XS, Wu HY, Yu HP, Zhou Q, Zhang YF, Huang Q. Expression of Lgr5 in human colorectal carcinogenesis and its potential correlation with β-catenin. Int J Colorectal Dis. 2010;25:583–90.CrossRefPubMed
27.
Zurück zum Zitat Steffen JS, Simon E, Warneke V, Balschun K, Ebert M, Rocken C. LGR4 and LGR6 are differentially expressed and of putative tumor biological significance in gastric carcinoma. Virchows Arch. 2012;461:355–65.CrossRefPubMed Steffen JS, Simon E, Warneke V, Balschun K, Ebert M, Rocken C. LGR4 and LGR6 are differentially expressed and of putative tumor biological significance in gastric carcinoma. Virchows Arch. 2012;461:355–65.CrossRefPubMed
28.
Zurück zum Zitat Gao Y, Kitagawa K, Hiramatsu Y, Kikuchi H, Isobe T, Shimada M, et al. Up-regulation of GPR48 induced by down-regulation of p27Kip1 enhances carcinoma cell invasiveness and metastasis. Cancer Res. 2006;66:11623–31.CrossRefPubMed Gao Y, Kitagawa K, Hiramatsu Y, Kikuchi H, Isobe T, Shimada M, et al. Up-regulation of GPR48 induced by down-regulation of p27Kip1 enhances carcinoma cell invasiveness and metastasis. Cancer Res. 2006;66:11623–31.CrossRefPubMed
29.
Zurück zum Zitat Polivka J Jr, Janku F. Molecular targets for cancer therapy in the PI3K/AKT/mTOR pathway. Pharmacol Ther. 2014;142:164–75.CrossRefPubMed Polivka J Jr, Janku F. Molecular targets for cancer therapy in the PI3K/AKT/mTOR pathway. Pharmacol Ther. 2014;142:164–75.CrossRefPubMed
30.
Zurück zum Zitat Sabbah DA, Brattain MG, Zhong H. Dual inhibitors of PI3K/mTOR or mTOR-selective inhibitors: which way shall we go? Curr Med Chem. 2011;18:5528–44.CrossRefPubMed Sabbah DA, Brattain MG, Zhong H. Dual inhibitors of PI3K/mTOR or mTOR-selective inhibitors: which way shall we go? Curr Med Chem. 2011;18:5528–44.CrossRefPubMed
31.
Zurück zum Zitat Jiang K, Zhong B, Ritchey C, Gilvary DL, Hong-Geller E, Wei S, et al. Regulation of Akt-dependent cell survival by Syk and Rac. Blood. 2003;101:236–44.CrossRefPubMed Jiang K, Zhong B, Ritchey C, Gilvary DL, Hong-Geller E, Wei S, et al. Regulation of Akt-dependent cell survival by Syk and Rac. Blood. 2003;101:236–44.CrossRefPubMed
33.
Zurück zum Zitat Gupta C, Kaur J, Tikoo K. Regulation of MDA-MB-231 cell proliferation by GSK-3β involves epigenetic modifications under high glucose conditions. Exp Cell Res. 2014;324:75–83.CrossRefPubMed Gupta C, Kaur J, Tikoo K. Regulation of MDA-MB-231 cell proliferation by GSK-3β involves epigenetic modifications under high glucose conditions. Exp Cell Res. 2014;324:75–83.CrossRefPubMed
Metadaten
Titel
GPCR48/LGR4 promotes tumorigenesis of prostate cancer via PI3K/Akt signaling pathway
verfasst von
Fang Liang
Junmin Yue
Junyong Wang
Lijuan Zhang
Rui Fan
Hao Zhang
Qingsong Zhang
Publikationsdatum
01.03.2015
Verlag
Springer US
Erschienen in
Medical Oncology / Ausgabe 3/2015
Print ISSN: 1357-0560
Elektronische ISSN: 1559-131X
DOI
https://doi.org/10.1007/s12032-015-0486-1

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