Essential role of Pyk2 and Src kinase activation in neuropeptide-induced proliferation of small cell lung cancer cells.
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 Cbeta 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.
Roelle
S
S
1Institut für Pharmakologie und Toxikologie, Philipps-Universität Marburg, Marburg, Germany.
Grosse
R
R
Buech
T
T
Chubanov
V
V
Gudermann
T
T
D002118:Calcium / Q000502:physiology; D018288:Carcinoma, Small Cell / Q000201:enzymology* / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004789:Enzyme Activation / Q000235:genetics; D051418:Focal Adhesion Kinase 2 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D019004:Galanin / Q000502:physiology*; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology* / Q000473:pathology; D011392:Proline / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism / Q000502:physiology*
C056567:GAL protein, human; D019004:Galanin; D011392:Proline; D051418:Focal Adhesion Kinase 2; D019061:src-Family Kinases; D002118:Calcium