Expression of V1A and GRP receptors leads to cellular transformation and increased sensitivity to substance-P analogue-induced growth inhibition

A C Mackinnon, U Tufail-hanif, Christopher Lucas, D Jodrell, C Haslett, T Sethi

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Small-cell lung cancer (SCLC) is a particularly aggressive cancer, which metastasises early. Despite initial sensitivity to radio- and chemo-therapy, it invariably relapses, so that the 2-year survival remains less than 5%. Neuropeptides particularly arginine vasopressin (AVP) and gastrin-releasing peptide (GRP) act as autocrine and paracrine growth factors and the expression of these and their receptors are a hallmark of the disease. Substance-P analogues including [D-Arg1,D-Phe5,D-Trp7,9,Leu11]-substance-P (SP-D) and [Arg6,D-Trp7,9,NmePhe8]-substance-P (6-11) (SP-G) inhibit the growth of SCLC cells by modulating neuropeptide signalling. We show that GRP and V1A receptors expression leads to the development of a transformed phenotype. Addition of neuropeptide provides some protection from etoposide-induced cytotoxicity. Receptor expression also leads to an increased sensitivity to substance-P analogue-induced growth inhibition. We show that SP-D and SP-G act as biased agonists at GRP and V1A receptors causing blockade of Gq-mediated Ca2+ release while directing signalling to activate ERK via a pertussis toxin-sensitive pathway. This is the first description of biased agonism at V1A receptors. This unique pharmacology governs the antiproliferative properties of these agents and highlights their potential therapeutic potential for the treatment of SCLC and particularly in tumours, which have developed resistance to chemotherapy.
Original languageEnglish
Pages (from-to)522-31
Number of pages10
JournalBritish Journal of Cancer
Volume92
Issue number3
DOIs
Publication statusPublished - 14 Feb 2005

Keywords / Materials (for Non-textual outputs)

  • Animals
  • Arginine Vasopressin
  • Cell Division
  • Cell Transformation, Neoplastic
  • Cricetinae
  • Cricetulus
  • Etoposide
  • Gastrin-Releasing Peptide
  • Humans
  • Peptide Fragments
  • Receptors, Neuropeptide
  • Substance P
  • Transfection
  • Tumor Cells, Cultured

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