Targeting V 1A-vasopressin receptors with [arg 6, D-Trp 7,9, N mePhe 8]-substance P (6-11) identifies a strategy to develop novel anti-cancer therapies

Alison C. MacKinnon, Uzma Tufail-Hanif, Mark Wheatley, Adriano G. Rossi, Christopher Haslett, Michael Seckl, Tariq Sethi

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Background and purpose: The anti-cancer agent [Arg 6, D-Trp 7,9, N mePhe 8]-substance P (6-11) (SP-G) modulates gastrin releasing peptide (GRP) and arginine vasopressin signalling in small cell lung cancer cells leading to growth arrest and apoptosis. We have shown that SP-G acts as a biased agonist at GRP receptors. This work examines the hypothesis that SP-G acts as a biased agonist at the V 1A vasopressin receptor. Experimental approach: The human V 1A receptor was expressed in CHO-K1 cells. Extracellular regulated kinase (ERK) activation and intracellular Ca 2+ were measured using activation state-specific antibodies and Fura-2-AM respectively. The effect of SP-G on tumourigenicity was assessed by colony assay. Key results: In V 1A receptor expressing cells, SP-G caused a sustained activation of ERK via a stimulation of V 1A receptor coupling to G i. Inhibition of G i with Pertussis toxin attenuated the inhibition by SP-G of the growth of CHO-K1 cells stably expressing the V 1A receptor. Chimeric V 1A receptors containing the second or third intracellular loop of the V 2 receptor were capable of binding vasopressin and SP-G but had altered ability to activate phospholipase C (PLC) and ERK. The second intracellular loop of the V 1A receptor was essential for vasopressin-stimulated PLC and ERK activation but not for SP-G-induced ERK activation. Conclusions and implications: This work provides mechanistic insight, for biased agonists at V 1A receptors and highlights a potential role for such agents as anti-cancer agents.

Original languageEnglish
Pages (from-to)36-47
Number of pages12
JournalBritish Journal of Pharmacology
Volume156
Issue number1
DOIs
Publication statusPublished - Jan 2009
Externally publishedYes

Keywords

  • [Arg , D-Trp , N Phe ]-substance P (6-11)
  • Biased agonist
  • Cancer
  • Directed signalling
  • V receptor
  • Vasopressin

ASJC Scopus subject areas

  • Pharmacology

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