title: Heterotrimeric G-protein, Gα16, is a critical downstream effector of non-canonical Wnt signaling and a potent inhibitor of transformed cell growth in non small cell lung cancer.
abstract: G-protein-coupled receptors (GPCR) are the largest family of cell surface molecules that play important role/s in a number of biological and pathological processes including cancers. Earlier studies have highlighted the importance of Wnt7a signaling via its cognate receptor Frizzled9, a GPCR, in inhibition of cell proliferation, anchorage-independent growth, and reversal of transformed phenotype in non small cell lung cancer primarily through activation of the tumor suppressor, PPARγ. However, the G-protein effectors that couple to this important tumor suppressor pathway have not been identified, and are of potential therapeutic interest. In this study, by using two independent Wnt7a/Frizzled9-specific read-outs, we identify Gα16 as a novel downstream effector of Wnt7a/Frizzled9 signaling. Interestingly, Gα16 expression is severely down-regulated, both at the messenger RNA levels and protein levels, in many non small cell lung cancer cell lines. Additionally, through gene-specific knock-downs and expression of GTPase-deficient forms (Q212L) of Gα16, we also establish Gα16 as a novel regulator of non small cell lung cancer cell proliferation and anchorage-independent cell growth. Taken together, our data not only establish the importance of Gα16 as a critical downstream effector of the non-canonical Wnt signaling pathway but also as a potential therapeutic target for the treatment of non small cell lung cancer.
authors.affiliation: Department of Pulmonary, Critical Care, Sleep and Allergy, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, United States of America.
authors.forename: Sreedevi
authors.initials: S
authors.lastname: Avasarala
authors.forename: Rama Kamesh
authors.initials: RK
authors.lastname: Bikkavilli
authors.forename: Michelle
authors.initials: M
authors.lastname: Van Scoyk
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Ajibike
authors.initials: A
authors.lastname: Lapite
authors.forename: Logan
authors.initials: L
authors.lastname: Hostetter
authors.forename: Joshua T
authors.initials: JT
authors.lastname: Byers
authors.forename: Lynn E
authors.initials: LE
authors.lastname: Heasley
authors.forename: Jang Won
authors.initials: JW
authors.lastname: Sohn
authors.forename: Robert A
authors.initials: RA
authors.lastname: Winn
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004789:Enzyme Activation; D051157:Frizzled Receptors / Q000235:genetics / Q000378:metabolism; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics / Q000378:metabolism*; D006131:Growth Inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D048054:Mitogen-Activated Protein Kinase 7 / Q000378:metabolism; D009154:Mutation; D047495:PPAR gamma / Q000378:metabolism; D034622:RNA Interference; D057050:Receptor Tyrosine Kinase-like Orphan Receptors / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway
chemical_list: C549560:FZD9 protein, human; D051157:Frizzled Receptors; D006131:Growth Inhibitors; D047495:PPAR gamma; C092778:WNT7A protein, human; D051153:Wnt Proteins; C078716:ROR1 protein, human; C078717:ROR2 protein, human; D057050:Receptor Tyrosine Kinase-like Orphan Receptors; D048054:Mitogen-Activated Protein Kinase 7; C112631:G protein alpha 16; D043802:GTP-Binding Protein alpha Subunits, Gq-G11