Cell Growth & Differentiation, Vol 7, Issue 7 923-929, Copyright © 1996 by American Association of Cancer Research

ARTICLES

Resistance to interleukin 6 in human non-small cell lung carcinoma cell lines: role of receptor components

MK Ganapathi, AK Weizer, S Borsellino, RM Bukowski, R Ganapathi, T Rice, G Casey and K Kawamura
Cancer Center Experimental Therapeutics Program, Cleveland Clinic Foundation, Ohio 44195, USA.

The role of interleukin 6 (IL-6) in regulating the growth of three human non-small cell lung carcinoma (NSCLC) cell lines (NSCLC-3, NSCLC-5, and NSCLC-7, derived from a primary lesion, a brain lesion, and lymph node metastases, respectively) was examined. Although IL-6 alone did not alter the growth of these cells, the addition of soluble IL-6 receptor (sIL-6R) led to the inhibition of proliferation of one of the NSCLC cell lines, NSCLC-5. This antiproliferative effect was neutralized by antibodies to IL-6 and the IL-6R binding and signaling component (gp130). The IL-6-related cytokines, leukemia inhibitory factor and oncostatin M, inhibited proliferation of NSCLC-5 cells but were ineffective in NSCLC-3 and NSCLC-7 cells. NSCLC-7 cells (but not NSCLC-3 or NSCLC-5 cells) secreted biologically active IL-6 and expressed IL-6R. However, antibodies to IL-6 or gp130 failed to alter the proliferation of NSCLC-7 cells. All three cell lines expressed gp130 mRNA and protein. The level of expression of gp130 protein varied in the three cell lines (NSCLC-7 > NSCLC-3 > NSCLC-5). The examination of tyrosine phosphorylation of gp130 (as an early event in IL-6 signal transduction) revealed that gp130 could be phosphorylated in all cell lines after stimulation with IL-6 and/or IL-6 + sIL-6R. These results demonstrate that the mechanisms responsible for IL-6 resistance in different NSCLC cell lines vary and involve defects at either one or more levels of the IL-6 signaling cascade. In the NSCLC-5 cell line, IL-6 resistance (which can be reversed in the presence of sIL-6R) is due to the transcriptional inactivation of the IL-6R gene. In contrast, in the other two cell lines (NSCLC-3 and NSCLC-7), defect(s) in the signaling cascade downstream of gp130 phosphorylation, together with a lack of expression of IL-6R in NSCLC-3 cells, result in IL-6 resistance.

This article has been cited by other articles:

				N. Underhill-Day and J. K. Heath Oncostatin M (OSM) Cytostasis of Breast Tumor Cells: Characterization of an OSM Receptor {beta}-Specific Kernel. Cancer Res., November 15, 2006; 66(22): 10891 - 10901. [Abstract] [Full Text] [PDF]

				M. Tabata, R. Tabata, D. R. Grabowski, R. M. Bukowski, M. K. Ganapathi, and R. Ganapathi Roles of NF-kappa B and 26 S Proteasome in Apoptotic Cell Death Induced by Topoisomerase I and II Poisons in Human Nonsmall Cell Lung Carcinoma J. Biol. Chem., March 9, 2001; 276(11): 8029 - 8036. [Abstract] [Full Text] [PDF]