Reactivation of epigenetically silenced SMAD1 contributes to chemosensitization. Reactivation of epigenetically silenced SMAD1 contributes to chemosensitization.

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Reactivation of epigenetically silenced SMAD1 contributes to chemosensitization. Reactivation of epigenetically silenced SMAD1 contributes to chemosensitization. A, representation of the change in the methylation (in %) of SMAD1 in chemoresistant OCI-Ly1, Karpas422, and SC-1 cells after treatment with decitabine for 72 hours, 120 hours, and 120 hours followed by a washout period of 120 hours (w.o.) compared with baseline methylation levels. B, immunoblot for SMAD1 (and GAPDH as control) for cells with dissimilar GI50 for doxorubicin (top). The ratio for the density of SMAD1 over GAPDH is shown at the bottom. C, immunoblot for SMAD1 in OCI-Ly1 and Karpas422 cells treated with vehicle (0 h) or decitabine for 72 and 120 hours. Whole-cell lysate and nuclear fraction are shown on top and bottom, respectively. GAPDH for whole-cell lysates and histone 3 for nuclear extracts were used as controls. D, cell viability of OCI-Ly1 and Karpas422 cells treated with vehicle or decitabine 100 nmol/L for 72 and 120 hours and treated with TGFβ1 and BMP2 for additional 24 hours. Data represent experimental triplicates. E, Differential viability of OCI-Ly1 cells transfected with SMAD1 or empty-vector (EV) plasmids and treated with water (vehicle), TGFβ1, or doxorubicin 600 nmol/L for 24 hours. Experiment represents the mean of triplicates with SEM. F, cell viability determined in OCI-Ly1, Karpas422, SC-1, and OCI-Ly10 cells transfected with SMAD1 2 μg or empty vector 2 μg (EV) for 24 hours and subsequently treated with doxorubicin 600 nmol/L or vehicle for additional 24 hours. Results are relative to EV + doxorubicin 600 nmol/L set as 100% viability. G, viability of OCI-Ly1 cells after 48 hours of transfection with si-NT or si-SMAD1 and treated with vehicle (UT) or several concentrations doxorubicin for 24 hours (10, 30, 125, 250, and 500 nmol/L). Thomas Clozel et al. Cancer Discovery 2013;3:1002-1019 ©2013 by American Association for Cancer Research