The oncostatin M receptor/gp130 ligand murine oncostatin M induces apoptosis in adrenocortical Y-1 tumor cells.
The effects of murine oncostatin M (mOSM) are specifically mediated by the heterodimeric oncostatin M receptor (OSMR)/gp130 receptor complex. In the current study we demonstrate that murine adrenocortical Y-1 tumor cells express the OSMR/gp130 complex. Incubation of Y-1 cells with 1 and 10 ng/ml mOSM induces cell death due to specific induction of apoptosis. Western blot analysis of Y-1 cells incubated with mOSM for 24 h revealed caspase-3 cleavage and poly(ADP-ribase) polymerase (PARP) cleavage. In a proliferation assay system, incubation of Y-1 cells with 0.01, 0.1, 1 and 10 ng/ml mOSM for 24 h resulted in a decrease in cell numbers to 99+/-2%, 84+/-9%, 50+/-7% and 43+/-5% respectively of untreated control (defined as 100%). Pretreatment of Y-1 cells with the Jak2 inhibitor AG490 (100 microM) rescued Y-1 cells from OSM-induced (10 ng/ml) cell death. Similarly, pretreatment of Y-1 cells with the general caspase inhibitor Z-VAD-FMK (42 microM) rescued Y-1 cells from OSM-induced (10 ng/ml) cell death. In summary, we show that adrenocortical Y-1 tumor cells express the OSMR/gp130 complex and that mOSM induces the Jak-STAT signaling cascade in these cells. Murine OSM in a dose-dependent manner induces apoptosis in adrenocortical Y-1 tumor cells. Apoptosis was demonstrated by caspase-3 cleavage and PARP cleavage. Rescue of Y-1 cells from mOSM-induced apoptosis by the Jak2 inhibitor, AG490, and the general caspase inhibitor, Z-VAD-FMK, demonstrates Jak activation and subsequent caspase activation to be essential for mOSM-induced apoptosis in adrenocortical Y-1 tumor cells. The putative role of OSM as an immunotherapeutic agent in human adrenocortical cancer remains to be elucidated.
Auernhammer
Christoph J
CJ
Department of Internal Medicine II, Klinikum Grosshadern, Ludwig-Maximilians-Universität, Marchioninistr. 15, Munich 81377, Germany. Christoph.Auernhammer@med2.meduni-muenchen.de
Dorn
Franziska
F
Vlotides
George
G
Hengge
Sabine
S
Kopp
Florian B
FB
Spoettl
Gerald
G
Cengic
Neziha
N
Engelhardt
Dieter
D
Weber
Matthias M
MM
D000306:Adrenal Cortex Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D050822:Cytokine Receptor gp130; D053614:Janus Kinase 2; D008562:Membrane Glycoproteins / Q000378:metabolism / Q000627:therapeutic use*; D051379:Mice; D053683:Oncostatin M; D010455:Peptides / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D015398:Signal Transduction / Q000187:drug effects; D020032:Tyrphostins / Q000494:pharmacology
D000590:Amino Acid Chloromethyl Ketones; D015703:Antigens, CD; D061945:Caspase Inhibitors; C494200:Il6st protein, mouse; D008562:Membrane Glycoproteins; C508351:OSM protein, human; C508352:Osm protein, mouse; D010455:Peptides; D011518:Proto-Oncogene Proteins; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D053683:Oncostatin M; D050822:Cytokine Receptor gp130; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D020169:Caspases