title: Mithramycin A inhibits myeloid cell leukemia-1 to induce apoptosis in oral squamous cell carcinomas and tumor xenograft through activation of Bax and oligomerization.
abstract: 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 (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) decreased TPA-induced JB6 cell transformation and Mcl-1 expression. Mcl-1 was overexpressed in human oral tumors compared with 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.
authors.affiliation: Assistant Professor, Department of Oral Pathology, School of Dentistry and Institute of Oral Bioscience, Chonbuk National University, Jeonju, 561-756, Republic of Korea.
authors.forename: Ji-Ae
authors.initials: JA
authors.lastname: Shin
authors.forename: Ji-Youn
authors.initials: JY
authors.lastname: Jung
authors.forename: Mi Heon
authors.initials: MH
authors.lastname: Ryu
authors.forename: Stephen
authors.initials: S
authors.lastname: Safe
authors.forename: Sung-Dae
authors.initials: SD
authors.lastname: Cho
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000473:pathology; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000378:metabolism; D009061:Mouth Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009062:Mouth Neoplasms / Q000188:drug therapy* / Q000473:pathology; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009368:Neoplasm Transplantation; D008926:Plicamycin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D058105:Polymerization; D021381:Protein Transport; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000235:genetics; D034622:RNA Interference; D014183:Transplantation, Heterologous; D051028:bcl-2-Associated X Protein / Q000819:agonists* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C066851:mithramycin A; D008926:Plicamycin