TY - JOUR T1 - Mithramycin A Inhibits Myeloid Cell Leukemia-1 to Induce Apoptosis in Oral Squamous Cell Carcinomas and Tumor Xenograft through Activation of Bax and Oligomerization JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.112.081364 SP - mol.112.081364 AU - Ji-Ae Shin AU - Ji-Youn Jung AU - Mi Heon Ryu AU - Stephen Safe AU - Sung-Dae Cho Y1 - 2012/01/01 UR - http://molpharm.aspetjournals.org/content/early/2012/09/27/mol.112.081364.abstract N2 - In several human malignancies, overexpression of myeloid cell leukemia-1 (Mcl-1) confers resistance to induction of apoptosis; however, Mcl-1-mediated inhibition of apoptosis in oral squamous cell carcinoma (OSCC) is not fully understood and has been investigated in this study. The Mcl-1 promoter activators, 12-O-tetradecanoylphorbol-13-acetate (TPA) and epidermal growth factor (EGF) enhanced neoplastic transformation of JB6 cells and this response was accompanied by enhanced expression of Mcl-1, and knockdown of Mcl-1 by RNA interference (RNAi) decreased JB6 cell transformation. In the same cell line, we also demonstrated that mithramycin A (Mith) decrease TPA-induced JB6 cell transformation and Mcl-1 expression. Mcl-1 was over-expressed in human oral tumors compared to normal oral mucosa and also in several OSCC cell lines including HN22 and HSC-4 cells. Treatment of these cells with Mith also decreased Mcl-1 expression and neoplastic cell transformation and this was accompanied by induction of several markers of apoptosis. Knockdown of Mcl-1 by RNAi also induced apoptotic cell death. The downregulation of Mcl-1 by Mith and RNAi increased pro-apoptotic protein Bax, resulting in the Bax translocation into mitochondria and its oligomerization. Mith also suppressed tumor growth in vivo and induced apoptosis in tumor by also regulating expression of Mcl-1 and Bax proteins. These indicate a critical role for Mcl-1 in the growth and survival of OSCC and demonstrate that Mith may be a potential anticancer drug candidate for clinical treatment of OSCC. ER -