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

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.

Regulation of Connexin-Based Channels by Fatty Acids

“…There is evidence in support of the participation of membrane receptors in the short-term effect on Cx-based channels (both GJCs and HCs). In some cases, the FA-mediated effect requires the participation of protein kinases that could be activated downstream of different GPCRs (Osmond et al, 2012; Suire et al, 2012; Liang et al, 2015), such as FA receptors (Itoh et al, 2003; Hirasawa et al, 2005). In agreement with such evidence, several protein kinases have been identified to modify Cxs (Solan and Lampe, 2014; Pogoda et al, 2016).…”

LGR4 Is a Direct Target of MicroRNA-34a and Modulates the Proliferation and Migration of Retinal Pigment Epithelial ARPE-19 Cells

“…[19] LGR4 promotes prostate tumorigenesis through PI3K/Akt signaling pathway. [16] Hsu et al identified a LGR4 splice variant which encodes a soluble secreted protein that can inhibit LGR4 mediated Wnt signaling. [27] Furthermore, a nonsense mutation of LGR4 (c.376C>T) has been reported to be strongly associated with low bone marrow density, electrolyte imbalance, reduced testosterone levels and increased risk of squamous cell carcinoma of the skin.…”

“…[12–15] The role of LGR4 in enhancing the aggressiveness of carcinoma as well as developmental derangements such as intrauterine growth retardation or renal development is well documented. [16–19] It has also been verified as a prognostic factor for poor outcome in cancer patients. [20] In terms of ocular development, we demonstrated that knockout of LGR4 reduced epithelial cell proliferation and migration and resulted in EOB (eye open at birth) phenotype in mice.…”

LGRs receptors as peculiar GPCRs involved in cancer

“…In cervical carcinoma cells, it correlates with enhanced cell migration and metastasis [97]. In the case of skin and prostate, LGR4 promotes tumorigenesis by modulating MEK/ERK and Wnt/β−catenin pathways and the PI3K/Akt cascade, respectively [98,99]. In colorectal cancer, LGR4 expression is markedly upregulated in moderately and poorly differentiated cells as well as at the tumor invasive front and in metastasis and it significantly correlates with nodal spread in gastric cancer [100][101][102].…”