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Small cell lung carcinoma exhibits greater phospholipase C-beta1 expression and edelfosine resistance compared with non-small cell lung carcinoma. Cancer Res 2000 May 15;60(10):2730-6

Date

05/29/2000

Pubmed ID

10825148

Scopus ID

2-s2.0-0034658432 (requires institutional sign-in at Scopus site)   47 Citations

Abstract

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)-beta1 is an early and common response to stimulation of G protein-coupled receptors by these neuroendocrine growth factors. The importance of PLC-beta in neuropeptide signaling prompted us to compare PLC-beta isoform expression and activity in four independent SCLC cell lines and four independent NSCLC cell lines. We found that PLC-beta1 is more highly expressed in SCLC than in NSCLC, as indicated by Western blotting of cell lysates. All SCLC lines studied express PLC-beta1; 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-beta1. The participation of PLC-beta1 in signaling by SCLC growth factor receptors is indicated by our finding that PLC-beta1 (but not PLC-beta3) coimnunoprecipitates with G(alpha)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 GTPgammaS to G(alpha)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(alpha)q/11 activation but rather inhibits the association of G(alpha)q/11 with PLC-beta1. Our data suggest that PLC-beta is an important mediator of both SCLC and NSCLC proliferation. Differences in PLC-beta1 expression may be exploitable in the development of effective diagnostic and therapeutic tools.

Author List

Strassheim D, Shafer SH, Phelps SH, Williams CL

Author

Carol L. Williams PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Antineoplastic Agents
Calcium
Carcinoma, Non-Small-Cell Lung
Carcinoma, Small Cell
Drug Resistance, Neoplasm
GTP-Binding Protein alpha Subunits, Gq-G11
GTP-Binding Proteins
Guanosine 5'-O-(3-Thiotriphosphate)
Humans
Isoenzymes
Lung Neoplasms
Phosphodiesterase Inhibitors
Phospholipase C beta
Phospholipid Ethers
Tumor Cells, Cultured
Type C Phospholipases