Resistance to interleukin 6 in human non-small cell lung carcinoma cell lines: role of receptor components.
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.
Ganapathi
M K
MK
Cancer Center Experimental Therapeutics Program, Cleveland Clinic Foundation, Ohio 44195, USA.
Weizer
A K
AK
Borsellino
S
S
Bukowski
R M
RM
Ganapathi
R
R
Rice
T
T
Casey
G
G
Kawamura
K
K
D015703:Antigens, CD / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000378:metabolism*; D051907:Lysosomal Membrane Proteins; D008562:Membrane Glycoproteins / Q000378:metabolism; D018123:Receptors, Interleukin / Q000378:metabolism*; D019947:Receptors, Interleukin-6; D014407:Tumor Cells, Cultured; D052118:Lysosomal-Associated Membrane Protein 1
D015703:Antigens, CD; D015850:Interleukin-6; D051907:Lysosomal Membrane Proteins; D008562:Membrane Glycoproteins; D018123:Receptors, Interleukin; D019947:Receptors, Interleukin-6; C489116:LAMP1 protein, human; D052118:Lysosomal-Associated Membrane Protein 1