Abstract 1350: Mitogen activated protein kinase activated protein kinase 2 (MK2) signaling in non-small cell lung carcinoma

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 ([Thr4,Gly7]OT) and V1aR (F180), in addition to OT and VP, were able to elicit increases in cytosolic Ca2+ 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 (p90RSK). Pre-incubation 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 Ca2+ 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 p90RSK phosphorylation. In [3H]thymidine-uptake experiments, we subsequently observed that PLC, Ca2+, 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 p90RSK in a PLC-, Ca2+-, PKC- and MEK1/2-dependent pathway.

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Calcium-dependent growth regulation of small cell lung cancer cells by neuropeptides

Endocrine Related Cancer ◽

10.1677/erc.1.01302 ◽

2006 ◽

Vol 13 (4) ◽

pp. 1069-1084 ◽

Cited By ~ 15

Author(s):

Thomas Gudermann ◽

Susanne Roelle

Keyword(s):

Protein Kinase ◽

Growth Regulation ◽

Hormone Receptors ◽

Apoptotic Cell ◽

Small Cell Lung Carcinoma ◽

Small Cell ◽

Mitogen Activated Protein Kinase ◽

Small Cell Lung ◽

Cell Lung Carcinoma ◽

Mitogenic Signal

Approximately 15–25% of all primary cancers of the lung are classified histologically as small cell lung carcinoma (SCLC), a subtype characterized by rapid growth and a poor prognosis. Neuropeptide hormones like bombesin/gastrin-releasing peptide, bradykinin or galanin are the principal mitogenic stimuli of this tumour entity. The mitogenic signal is transmitted into the cell via heptahelical neuropeptide hormone receptors, which couple to the heterotrimeric G proteins of the Gq/11 familiy. Subsequent activation of phospholipase Cβ (PLCβ) entails the activation of protein kinase C and the elevation of the intracellular calcium concentration. There is mounting evidence to support the notion that calcium mobilization is the key event that initiates different mitogen-activated protein kinase cascades. Neuropeptide-dependent proliferation of SCLC cells relies on parallel activation of the Gq/11/PLCβ/Ras/extracellular signal-regulated kinase and the c-jun N-terminal kinase pathways, while selective engagement of either signalling cascade alone results in growth arrest and differentiation or apoptotic cell death. Basic experimental research has the potential to identify and validate novel therapeutic targets located at critical points of convergence of different mitogenic signal transduction pathways. In the case of SCLC, targeting the distinct components of the Ca2+ influx pathway as well as critical Ca2+-dependent cellular effectors may be rewarding in this regard.

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Regulation of Integrin-Mediated Adhesion by Muscarinic Acetylcholine Receptors and Protein Kinase C in Small Cell Lung Carcinoma

CHEST Journal ◽

10.1378/chest.114.3.839 ◽

1998 ◽

Vol 114 (3) ◽

pp. 839-846 ◽

Cited By ~ 17

Author(s):

Robert L. Quigley ◽

Shulamith H. Shafer ◽

Carol L. Williams

Keyword(s):

Protein Kinase C ◽

Protein Kinase ◽

Lung Carcinoma ◽

Acetylcholine Receptors ◽

Small Cell Lung Carcinoma ◽

Small Cell ◽

Muscarinic Acetylcholine Receptors ◽

Small Cell Lung ◽

Cell Lung Carcinoma ◽

Kinase C

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Mechanisms of mitogen-activated protein kinase activation by nicotine in small-cell lung carcinoma cells

Biochemical Journal ◽

10.1042/bj3280499 ◽

1997 ◽

Vol 328 (2) ◽

pp. 499-503 ◽

Cited By ~ 46

Author(s):

G. Maria CATTANEO ◽

Fabio D'ATRI ◽

M. Lucia VICENTINI

Keyword(s):

Tyrosine Kinase ◽

Map Kinase ◽

Lung Carcinoma ◽

Pertussis Toxin ◽

Nicotinic Receptors ◽

Small Cell Lung Carcinoma ◽

Small Cell ◽

Small Cell Lung ◽

Cell Lung Carcinoma ◽

Mitogen Activated Protein

We have previously reported that nicotine stimulates cell proliferation of three small-cell lung carcinoma (SCLC) cell lines by activating nicotinic receptors of the neuronal type. Here we report that, in the GLC-8 SCLC cell line, nicotine stimulates mitogen-activated protein (MAP) kinase activity in a concentration- and time-dependent manner (ED50 = 10 nM). The nicotine effect was antagonized by mecamylamine, an antagonist specific for neuronal nicotinic receptors. The absence of extracellular Ca2+, or pretreatment with pertussis toxin or the tyrosine kinase inhibitor genistein inhibited the action of nicotine on MAP kinase. Moreover, supernatants from nicotine-stimulated cells transferred to cells pretreated with mecamylamine were still capable of activating MAP kinase. On the other hand, the same supernatants transferred to cells pretreated with mecamylamine and pertussis toxin or genistein failed to activate MAP kinase. These findings suggest that nicotine elicits its stimulatory effect on MAP kinase in SCLC cells indirectly by inducing the production and/or release of a factor which then acts via a pertussis toxin- and tyrosine kinase-sensitive route.

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