title: Targeting ERK1/2-bim signaling cascades by BH3-mimetic ABT-737 as an alternative therapeutic strategy for oral cancer.
abstract: To date, many different chemotherapeutic agents have been widely used as common treatments for oral cancers. However, their therapeutic effects have been disappointing, and these agents may have unwanted side effects. Among the many regulatory factors, overexpression of pro-survival Bcl-2 family members may promote resistance to chemotherapeutic drugs in many tumors. The BH3 domain-only proteins effectively antagonize their apoptotic activities. Therefore, there is substantial interest in developing chemotherapeutic drugs that directly target pro-survival Bcl-2 proteins by mimicking the BH3 domain and unleashing pro-apoptotic molecules in tumor cells. Among the numerous available small molecule BH3 mimetics, ABT-737, a potent small molecule that binds to Bcl-2/Bcl-xL with high affinity, has anti-tumor activity in a wide variety of cancer cells. However, the effects of ABT-737 on human oral cancers and the underlying molecular mechanisms have not previously been elucidated. In the present study, we observed that inactivation of the ERK1/2 signaling pathway using ABT-737 dramatically increased the expression of pro-apoptotic protein Bim via transcriptional and/or posttranslational regulation, in a cell type-dependent manner, inducing mitochondria-mediated apoptosis of human oral cancer cells. To the best of our knowledge, this is the first demonstration of the antitumor effects of ABT-737 on human oral cancers.
authors.affiliation: Department of Oral Pathology, School of Dentistry, Institute of Biodegradable Material, Institute of Oral Bioscience, Chonbuk National University, Jeonju, Republic of Korea.
authors.forename: Ji-Ae
authors.initials: JA
authors.lastname: Shin
authors.affiliation: Department of Oral Pathology, School of Dentistry, Institute of Biodegradable Material, Institute of Oral Bioscience, Chonbuk National University, Jeonju, Republic of Korea.
authors.forename: Lee-Han
authors.initials: LH
authors.lastname: Kim
authors.affiliation: Department of New Drug Discovery and Development, Chungnam National University, Daejon, Republic of Korea.
authors.forename: Sook-Jeong
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Department of Dermatology and Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Jeong
authors.affiliation: Department of Companion and Laboratory Animal Science, Kongju National University, Yesan, Republic of Korea.
authors.forename: Ji-Youn
authors.initials: JY
authors.lastname: Jung
authors.affiliation: Department of Companion and Laboratory Animal Science, Kongju National University, Yesan, Republic of Korea.
authors.forename: Hae Nim
authors.initials: HN
authors.lastname: Lee
authors.affiliation: Department of Molecular Medicine, School of Medicine, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Republic of Korea.
authors.forename: In-Sun
authors.initials: IS
authors.lastname: Hong
authors.affiliation: Department of Oral Pathology, School of Dentistry, Institute of Biodegradable Material, Institute of Oral Bioscience, Chonbuk National University, Jeonju, Republic of Korea.
authors.forename: Sung-Dae
authors.initials: SD
authors.lastname: Cho
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D032701:Biomimetics; D001713:Biphenyl Compounds / Q000494:pharmacology*; D018277:Carcinoma, Mucoepidermoid / Q000188:drug therapy*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy*; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D058990:Molecular Targeted Therapy; D009062:Mouth Neoplasms / Q000188:drug therapy*; D009596:Nitrophenols / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: C501332:ABT-737; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D051023:BH3 Interacting Domain Death Agonist Protein; D000072224:Bcl-2-Like Protein 11; D001713:Biphenyl Compounds; D008565:Membrane Proteins; D009596:Nitrophenols; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides
keywords: ABT-737; BH3 mimetics; Bcl-2 family; apoptosis; oral cancer