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Regulation of Cellular Proliferation, Cytoskeletal Function, and Signal Transduction through CXCR4 and c-Kit in Small Cell Lung Cancer Cells

Department of Adult Oncology [T. K., G. M., P. C. M., R. E. T., B. R., M. S., B. E. J., R. S.], and Department of Immunobiology [E. V. T.], Dana-Farber Cancer Institute, and Department of Medicine, Brigham and Women’s Hospital, and Harvard Medical School, Boston, Massachusetts 02115, and Division of Hematology and Oncology, Tufts-New England Medical Center, Boston, Massachusetts 02111 [P. C. M.]

The regulation of biological functions including cell growth, viability, migration, and adhesion of small cell lung cancer (SCLC) cells depends largely on the autocrine or paracrine stimulation of growth factor receptors and chemokine receptors. Stem cell factor (SCF) and its receptor c-Kit have been identified as important regulators of SCLC viability and are coexpressed in approximately 40–70% of SCLC specimens. In vitro, the inhibition of c-Kit tyrosine kinase activity by the small molecule tyrosine kinase inhibitor STI571 (Gleevec) abrogates cell growth. We have investigated the role of c-Kit and chemokine receptors in the regulation of cell migration and adhesion of SCLC cells. CXCR4, the chemokine receptor for stromal cell-derived factor-1 (SDF-1), was found to be the major chemokine receptor commonly expressed in all of the 10 SCLC cell lines tested. SCF and SDF-1 increased cellular proliferation over a course of 72 h in both the c-Kit- and the CXCR4-positive NCI-H69 SCLC cell line. Recently, SDF-1 and CXCR4 have been shown to be important regulators of migration and metastasis in breast and ovarian cancer. We found that SDF-1 dramatically increased cell motility and adhesion in CXCR4-expressing NCI-H446 SCLC cells. In addition, SDF-1 altered cell morphology with increased formation of filopodia and neurite-like projections. In NCI-H69 SCLC cells, SCF and SDF-1 cooperatively induced morphological changes and activated downstream signaling pathways. Treatment of NCI-H69 cells with STI571 specifically inhibited the c-Kit signaling events of Akt and p70 S6 kinase, whereas SDF-1-mediated activation of Akt or p70 S6 kinase was normal. In contrast, the phosphatidylinositol 3-kinase inhibitor, LY294002, prevented these cells from adhering and completely blocked SCF- and/or SDF-1-induced Akt or p70 S6 kinase phosphorylation. These results demonstrate that the CXCR4 receptor is functionally expressed in SCLC cells and may, therefore, be involved in the pathogenesis of SCLC in vivo. Inhibition of both the CXCR4 and the c-Kit downstream events could be a promising therapeutic approach in SCLC.

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