TY - JOUR
T1 - 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
AU - MacKinnon, Alison C.
AU - Tufail-Hanif, Uzma
AU - Wheatley, Mark
AU - Rossi, Adriano G.
AU - Haslett, Christopher
AU - Seckl, Michael
AU - Sethi, Tariq
PY - 2009/1
Y1 - 2009/1
N2 - 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.
AB - 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.
KW - [Arg , D-Trp , N Phe ]-substance P (6-11)
KW - Biased agonist
KW - Cancer
KW - Directed signalling
KW - V receptor
KW - Vasopressin
UR - http://www.scopus.com/inward/record.url?scp=65549098719&partnerID=8YFLogxK
U2 - 10.1111/j.1476-5381.2008.00003.x
DO - 10.1111/j.1476-5381.2008.00003.x
M3 - Article
C2 - 19133990
AN - SCOPUS:65549098719
VL - 156
SP - 36
EP - 47
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
SN - 0007-1188
IS - 1
ER -