Targeting V1A-vasopressin receptors with [Arg6, D-Trp7,9, NmePhe8]-substance P (6-11) identifies a strategy to develop novel anti-cancer therapies.

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 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.