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Small Cell Lung Carcinoma Exhibits Greater Phospholipase C-ß1 Expression and Edelfosine Resistance Compared with Non-Small Cell Lung Carcinoma¹

Molecular Pharmacology Laboratory, Guthrie Research Institute, Sayre, Pennsylvania 18840

Aberrant signal transduction pathways involved in the development of metastatic disease are poorly defined in both small cell lung carcinoma (SCLC) and non-small cell lung carcinoma (NSCLC). Neuropeptide-driven positive feedback loops stimulating cell proliferation are characteristic of SCLC. The activation of phospholipase C (PLC)-ß is an early and common response to stimulation of G protein-coupled receptors by these neuroendocrine growth factors. The importance of PLC-ß in neuropeptide signaling prompted us to compare PLC-ß isoform expression and activity in four independent SCLC cell lines and four independent NSCLC cell lines. We found that PLC-ß1 is more highly expressed in SCLC than in NSCLC, as indicated by Western blotting of cell lysates. All SCLC lines studied express PLC-ß1; only one of the NSCLC lines investigated showed detectable levels of the enzyme. NSCLC lines are significantly more sensitive to the antiproliferative effects of ET-18-OCH₃ (edelfosine) compared with the SCLC lines, as indicated by [³H]thymidine uptake. The only SCLC cell line (NCI-H345) that is as sensitive as the NSCLC cell lines to ET-18-OCH₃ also expresses uniquely low levels of PLC-ß1. The participation of PLC-ß1 in signaling by SCLC growth factor receptors is indicated by our finding that PLC-ß1 (but not PLC-ß3) coimmunoprecipitates with G_q/11 upon activation of neurotensin receptors; this association is inhibited by ET-18-OCH₃. Ca²⁺ mobilization mediated by neurotensin receptors is also inhibited by ET-18-OCH₃. The binding of GTPS to G_q/11 upon treatment of SCLC cells with neurotensin is not inhibited by ET-18-OCH₃. These findings indicate that ET-18-OCH₃ does not interfere with G_q/11 activation but rather inhibits the association of G_q/11 with PLC-ß1. Our data suggest that PLC-ß is an important mediator of both SCLC and NSCLC proliferation. Differences in PLC-ß1 expression may be exploitable in the development of effective diagnostic and therapeutic tools.

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