title: Orphan G protein-coupled receptor GPR56 plays a role in cell transformation and tumorigenesis involving the cell adhesion pathway.
abstract: GPR56 is an orphan G protein - coupled receptor, mutations of which have recently been associated with bilateral frontoparietal polymicrogyria, a rare neurologic disease that has implications in brain development. However, no phenotype beyond central nervous system has yet been described for the GPR56-null mutations despite abundant GPR56 expression in many non - central nervous system adult tissues. In the present study, we show that higher GPR56 expression is correlated with the cellular transformation phenotypes of several cancer tissues compared with their normal counterparts, implying a potential oncogenic function. RNA interference-mediated GPR56 silencing results in apoptosis induction and reduced anchorage-independent growth of cancer cells via increased anoikis, whereas cDNA overexpression resulted in increased foci formation in mouse fibroblast NIH3T3 cell line. When GPR56 silencing was induced in vivo in several xenograft tumor models, significant tumor responses (including regression) were observed, suggesting the potential of targeting GPR56 in the development of tumor therapies. The expression profiling of GPR56-silenced A2058 melanoma cell line revealed several genes whose expression was affected by GPR56 silencing, particularly those in the integrin-mediated signaling and cell adhesion pathways. The potential role of GPR56 in cancer cell adhesion was further confirmed by the observation that GPR56 silencing also reduced cell adhesion to the extracellular matrix, which is consistent with the observed increase in anoikis and reduction in anchorage-independent growth phenotypes. The oncogenic potential and apparent absence of physiologic defects in adult human tissues lacking GPR56, as well as the targetable nature of G protein - coupled receptor by small molecule or antibody, make GPR56 an attractive drug target for the development of cancer therapies.
authors.affiliation: Immusol, Inc., San Diego, CA 92121, USA.
authors.forename: Ning
authors.initials: N
authors.lastname: Ke
authors.forename: Roshni
authors.initials: R
authors.lastname: Sundaram
authors.forename: Guohong
authors.initials: G
authors.lastname: Liu
authors.forename: John
authors.initials: J
authors.lastname: Chionis
authors.forename: Wufang
authors.initials: W
authors.lastname: Fan
authors.forename: Cheryl
authors.initials: C
authors.lastname: Rogers
authors.forename: Tarif
authors.initials: T
authors.lastname: Awad
authors.forename: Mirta
authors.initials: M
authors.lastname: Grifman
authors.forename: Dehua
authors.initials: D
authors.lastname: Yu
authors.forename: Flossie
authors.initials: F
authors.lastname: Wong-Staal
authors.forename: Qi-Xiang
authors.initials: QX
authors.lastname: Li
mesh_terms: D000818:Animals; D001483:Base Sequence; D002448:Cell Adhesion; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D017931:DNA Primers; D020869:Gene Expression Profiling; D020868:Gene Silencing; D006801:Humans; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D017931:DNA Primers; C513334:GPR65 protein, human; D043562:Receptors, G-Protein-Coupled