title: Cross talk between the bombesin neuropeptide receptor and Sonic hedgehog pathways in small cell lung carcinoma.
abstract: Small cell lung carcinoma (SCLC) often features the upregulation of the Sonic hedgehog (Shh) pathway leading to activation of Gli transcription factors. SCLC cells secrete bombesin (BBS)-like neuropeptides that act as autocrine growth factors. Here, we show that SCLC tumor samples feature co-expression of Shh and BBS-cognate receptor (gastrin-releasing peptide receptor (GRPR)). We also demonstrate that BBS activates Gli in SCLC cells, which is crucial for BBS-mediated SCLC proliferation, because cyclopamine, an inhibitor of the Shh pathway, hampered the BBS-mediated effects. BBS binding to GRPR stimulated Gli through its downstream Gαq and Gα₁₂/₁₃ GTPases, and consistently, other Gαq and Gα₁₃ coupled receptors (such as muscarinic receptor, m1, and thrombin receptor, PAR-1) and constitutively active GαqQL and Gα₁₂/₁₃QL mutants stimulated Gli. By using cells null for Gαq and Gα₁₂/₁₃, we demonstrate that these G proteins are strictly necessary for Gli activation by BBS. Moreover, by using constitutively active Rho small G-protein (Rho QL) as well as its inhibitor, C3 toxin, we show that Rho mediates G-protein-coupled receptor (GPCR)-, Gαq- and Gα₁₂/₁₃-dependent Gli stimulation. At the molecular level, BBS caused a significant increase in Shh gene transcription and protein secretion that was dependent on BBS-induced GPCR/Gαq-₁₂/₁₃/Rho mediated activation of nuclear factor κB (NFκB), which can stimulate a NF-κB response element in the Shh gene promoter. Our data identify a novel molecular network acting in SCLC linking autocrine BBS and Shh circuitries and suggest Shh inhibitors as novel therapeutic strategies against this aggressive cancer type.
authors.affiliation: 1] Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA [2] Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Istituto di Endocrinologia ed Oncologia Sperimentale "G. Salvatore" (IEOS), University of Naples "Federico II", Naples, Italy.
authors.forename: M D
authors.initials: MD
authors.lastname: Castellone
authors.affiliation: SDN Foundation, Naples, Italy.
authors.forename: M O
authors.identifier: 0000000210047131
authors.initials: MO
authors.lastname: Laukkanen
authors.affiliation: 1] Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA [2] Department of Internal Medicine, Kojin Hospital, Nagoya, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Teramoto
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Istituto di Endocrinologia ed Oncologia Sperimentale "G. Salvatore" (IEOS), University of Naples "Federico II", Naples, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Bellelli
authors.affiliation: Division of Pathological Anatomy, Department of Surgery, University of Pisa, Pisa, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Alì
authors.affiliation: Division of Pathological Anatomy, Department of Surgery, University of Pisa, Pisa, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Fontanini
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Istituto di Endocrinologia ed Oncologia Sperimentale "G. Salvatore" (IEOS), University of Naples "Federico II", Naples, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Santoro
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Gutkind
mesh_terms: D000818:Animals; D001839:Bombesin / Q000494:pharmacology; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D002945:Cisplatin / Q000494:pharmacology; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000502:physiology; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000502:physiology; D057809:HEK293 Cells; D053823:Hedgehog Proteins / Q000502:physiology*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology*; D051379:Mice; D041681:NIH 3T3 Cells; D015513:Oncogene Proteins / Q000502:physiology; D011719:Pyrazines / Q000494:pharmacology; D018004:Receptors, Bombesin / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy / Q000473:pathology*; D015534:Trans-Activators / Q000502:physiology; D000071676:Zinc Finger Protein GLI1
chemical_list: D001897:Boronic Acids; D053823:Hedgehog Proteins; D015513:Oncogene Proteins; D011719:Pyrazines; D018004:Receptors, Bombesin; D015534:Trans-Activators; D000071676:Zinc Finger Protein GLI1; D000069286:Bortezomib; D044365:GTP-Binding Protein alpha Subunits, G12-G13; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D001839:Bombesin; D002945:Cisplatin
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