Targeting ERK1/2-bim signaling cascades by BH3-mimetic ABT-737 as an alternative therapeutic strategy for oral cancer

// Ji-Ae Shin 1, * , Lee-Han Kim 1, * , Sook-Jeong Lee 2, * , Joseph H. Jeong 3 , Ji-Youn Jung 4 , Hae Nim Lee 4 , In-Sun Hong 5 , Sung-Dae Cho 1 1 Department of Oral Pathology, School of Dentistry, Institute of Biodegradable Material, Institute of Oral Bioscience, Chonbuk National University, Jeonju, Republic of Korea 2 Department of New Drug Discovery and Development, Chungnam National University, Daejon, Republic of Korea 3 Department of Dermatology and Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA 4 Department of Companion and Laboratory Animal Science, Kongju National University, Yesan, Republic of Korea 5 Department of Molecular Medicine, School of Medicine, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Republic of Korea * These authors have contributed equally to this work Correspondence to: In-Sun Hong, e-mail: hongstem@gachon.ac.kr Sung-Dae Cho, e-mail: efiwdsc@chonbuk.ac.kr Keywords: BH3 mimetics, ABT-737, oral cancer, apoptosis, Bcl-2 family Received: July 03, 2015      Accepted: September 21, 2015      Published: October 02, 2015 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.