Targeting V-1A-vasopressin receptors with [Arg(6), D-Trp(7,9), N(me)Phe(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 journalArticlepeer-review

Abstract

Background and purpose: The anti-cancer agent [Arg(6), D-Trp(7,9), N(me)Phe(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 Ca2+ 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 Gi 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

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