Expression of V(1A) and GRP receptors leads to cellular transformation and increased sensitivity to substance-P analogue-induced growth inhibition

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-Arg(1),D-Phe(5),D-Trp(7,9),Leu(11)]-substance-P (SP-D) and [Arg(6),D-Trp(7,9),N(me)Phe(8)]-substance-P (6–11) (SP-G) inhibit the growth of SCLC cells by modulating neuropeptide signalling. We show that GRP and V(1A) 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 V(1A) receptors causing blockade of G(q)-mediated Ca(2+) release while directing signalling to activate ERK via a pertussis toxin-sensitive pathway. This is the first description of biased agonism at V(1A) 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.