Oncotarget

Research Papers:

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

Ji-Ae Shin _, Lee-Han Kim, Sook-Jeong Lee, Joseph H. Jeong, Ji-Youn Jung, Hae Nim Lee, In-Sun Hong and Sung-Dae Cho

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Oncotarget. 2015; 6:35667-35683. https://doi.org/10.18632/oncotarget.5523

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Abstract

Ji-Ae Shin1,*, Lee-Han Kim1,*, Sook-Jeong Lee2,*, Joseph H. Jeong3, Ji-Youn Jung4, Hae Nim Lee4, In-Sun Hong5, Sung-Dae Cho1

1Department of Oral Pathology, School of Dentistry, Institute of Biodegradable Material, Institute of Oral Bioscience, Chonbuk National University, Jeonju, Republic of Korea

2Department of New Drug Discovery and Development, Chungnam National University, Daejon, Republic of Korea

3Department of Dermatology and Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA

4Department of Companion and Laboratory Animal Science, Kongju National University, Yesan, Republic of Korea

5Department 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.


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