1. ¹Institut für Pharmakologie und Toxikologie, Philipps-Universität Marburg, Marburg, Germany
2. ²Pharmakologisches Institut, Ruprecht-Karls-Universität Heidelberg, Heidelberg, Germany

Correspondence: Professor Dr T Gudermann, Institut für Pharmakologie und Toxikologie, Philipps-Universität Marburg, Karl-von-Frisch-Strae 1, Marburg 35043, Germany. E-mail: guderman@staff.uni-marburg.de

Received 25 January 2007; Revised 12 July 2007; Accepted 16 August 2007; Published online 1 October 2007.

Abstract

Neuropeptide hormones like bombesin/gastrin-releasing peptide, galanin or bradykinin, acting via auto and paracrine growth loops, represent the principal mitogens of small cell lung cancer (SCLC). These mitogenic neuropeptides activate G_q/11-coupled receptors which stimulate phospholipase C activity, followed by rises of the intracellular calcium concentration ([Ca²⁺]_i) and activation of protein kinase C (PKC). We report here that proline-rich tyrosine kinase Pyk2 is highly expressed in SCLC cells and provides a functional link between neuropeptide-induced increases in [Ca²⁺]_i and tumor cell proliferation. Activation of Pyk2 and its association with Src kinases critically depends on the elevation of [Ca²⁺]_i, but is independent of PKC. Src kinase activities are crucial for neuropeptide-mediated GTP-loading of Ras and activation of extracellular signal-regulated kinases in SCLC cells. Pyk2 and Src kinases essentially contribute to anchorage-independent proliferation of SCLC cells. Inhibition of either Pyk2 or Src kinases by lentiviral RNAi or pharmacological inhibition with PP2, respectively, attenuated basal and neuropeptide-elicited survival and proliferation of SCLC cells in liquid culture and in soft agar. Thus, neuropeptides stimulate anchorage-independent survival and proliferation of SCLC cells via pathways involving Pyk2 and Src kinases. Therefore, Ca²⁺-induced Pyk2/Src complex formation may be a rewarding molecular target for novel therapeutic strategies in SCLC cells.