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.

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