Oxytocin- and vasopressin-induced growth of human small-cell lung cancer is mediated by the mitogen-activated protein kinase pathway

Abstract

Malignant growth of small-cell lung carcinoma is promoted by various neuroendocrine autocrine/ paracrine loops. Therefore, to interfere with this mitogenic process, it is crucial to elucidate the mechanisms involved. It is known that the oxytocin (OT) and vasopressin (VP) genes, normally transcriptionally restricted in their expression, are activated in small-cell lung cancer (SCLC), concomitantly with expression of their receptors (OTR, V1aR, V1bR/V3R and V2R). The aim of the present study was to characterize, in concentrations close to physiological and pharmacological conditions, intracellular signalling events triggered by OT and VP binding to their specific receptors in SCLC cells and to identify factors mediating OT-and VP-induced mitogenic effects on SCLC. Known agonists for OTR ([Thr 4 ,Gly 7 ]OT) and V1aR (F180), in addition to OT and VP, were able to elicit increases in cytosolic Ca 2+ levels and this effect could be blocked using an OTR antagonist (OVTA) or a V1aR antagonist (SR49059) respectively. There was no activation of the cAMP pathway detected after VP, dDAVP (a V2R agonist), or OT treatment. Stimulation of SCLC cells with OT and VP led to an increase of extracellular signal-regulated kinase (ERK) 1/2 phosphorylation, maximal at 5 min, and the subsequent phosphorylation of its downstream target p90 ribosomal S6 kinase (p90 RSK ). Preincubation with OVTA and SR49059, and with inhibitors of phospholipase C (PLC), protein kinase C (PKC), mitogen-activated protein kinase/ERK kinase (MEK) 1/2 and a Ca 2+ chelator significantly reduced OT-and VP-induced ERK1/2 phosphorylations. OVTA, SR49059 as well as MEK1/2 and PKC inhibitors also downregulated OT-and VP-induced p90 RSK phosphorylation. In [ 3 H]thymidine-uptake experiments, we subsequently observed that PLC, Ca 2+ , PKC and ERK1/2 are absolutely required for the OT-and VP-stimulated SCLC cellular growth process. In conclusion, the results presented here indicate that OT-and VP-induced mitogenic effects on SCLC are respectively mediated by OTR and V1aR signalling and that this mitogenic signalling passes through the phosphorylation of ERK1/2 and p90 RSK in a PLC-, Ca 2+ -, PKC-and MEK1/2-dependent pathway.

Provasopressin expression by breast cancer cells: implications for growth and novel treatment strategies

“…However, exogenous AVP was found to activate ERK1/2 and increase the proliferation of these cells, which was comparable to what we observed with SCLC cells [19]. Activation of the V1a receptor has been shown to increase the levels of phosphorylated ERK1/2 and mediate the AVP-induced proliferation of SCLC cells, intestinal epithelial cells, and in V1a receptor-transfected cells [19,[58][59][60]. Our results suggest that a similar growth promoting mechanism occurs in breast cancer cells in response to AVP.…”

“…AVP (10 nM) increased Mcf7 and Skbr3 cell proliferation by approximately 8% and 15% at day 1, and by approximately 22% and 19% at day 3, respectively. The increase observed at day 3 is comparable to what we observed for H345 and H146 SCLC cells [19]. We have shown that AVP-induced SCLC cell proliferation is mediated by the V1a receptor [19].…”

“…The increase observed at day 3 is comparable to what we observed for H345 and H146 SCLC cells [19]. We have shown that AVP-induced SCLC cell proliferation is mediated by the V1a receptor [19]. Therefore, the V1a receptor antagonist SR49059 was used to examine the impact of endogenous and exogenous AVP on breast cancer cell proliferation.…”

“…Recently, we demonstrated that AVP activated ERK1/2 in SCLC cells and increased their proliferation [19]. (Figure 7a).…”

Neuroendocrine influences on cancer biology

“…breast, endometrial) tumors and those of nervous or bone origin, but it has a proliferative effect on trophoblast and other tumors (e.g. small cell lung tumors, Kaposi's sarcoma) [77,78]. The presence of the oxytocin receptor has been described on breast and prostate cancer cells [79][80][81].…”