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 Gq/11-coupled receptors which stimulate phospholipase Cβ 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.
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Abbreviations
- ERK:
-
extracellular signal-regulated kinase
- FAK:
-
focal adhesion kinase
- GEF:
-
guanine nucleotide exchange factor
- Grb2:
-
growth factor receptor-bound protein 2
- GRP:
-
bombesin/gastrin-releasing peptide
- JNK/SAPK:
-
c-jun N-terminal kinase/stress-activated kinase
- MAPK:
-
mitogen-activated protein kinase
- MEK:
-
MAPK/ERK kinase
- N-SCLC:
-
Non-small cell lung cancer
- PI3K:
-
phosphatidylinositol 3-kinase
- PKC:
-
protein kinase C
- PLC:
-
phospholipase C
- RasGRF:
-
Ras guanine nucleotide-releasing factor
- RasGRP:
-
Ras guanine nucleotide-releasing protein
- RBD:
-
Ras-binding domain
- SCLC:
-
small cell lung cancer
- SH2 and SH3:
-
Src homology domain
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The study was supported by a grant from the Deutsche Forschungsgemeinschaft.
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Roelle, S., Grosse, R., Buech, T. et al. Essential role of Pyk2 and Src kinase activation in neuropeptide-induced proliferation of small cell lung cancer cells. Oncogene 27, 1737–1748 (2008). https://doi.org/10.1038/sj.onc.1210819
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DOI: https://doi.org/10.1038/sj.onc.1210819
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