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Int. J. Mol. Sci. 2017, 18(1), 44; doi:10.3390/ijms18010044

Obatoclax, a Pan-BCL-2 Inhibitor, Targets Cyclin D1 for Degradation to Induce Antiproliferation in Human Colorectal Carcinoma Cells

1
Institute of Biomedical Sciences, National Chung Hsing University, 145 Xingda Road, Taichung 40227, Taiwan
2
Department of Life Science, National Chung Hsing University, 145 Xingda Road, Taichung 40227, Taiwan
3
Department of Anesthesiology, Kuang Tien General Hospital, Dajia Branch, 321 Jingguo Road, Taichung 43761, Taiwan
4
Ph.D. Program in Translational Medicine, National Chung Hsing University, 145 Xingda Road, Taichung 40227, Taiwan
5
Agricultural Biotechnology Center, National Chung Hsing University, 145 Xingda Road, Taichung 40227, Taiwan
6
Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, 145 Xingda Road, Taichung 40227, Taiwan
7
Department of Medical Research, China Medical University Hospital, 2 Yude Road, Taichung 40447, Taiwan
8
Department of Biotechnology, Asia University, 500 Liufeng Road, Taichung 41354, Taiwan
*
Author to whom correspondence should be addressed.
Academic Editor: Hsueh-Wei Chang
Received: 16 November 2016 / Revised: 19 December 2016 / Accepted: 21 December 2016 / Published: 27 December 2016
(This article belongs to the Special Issue Tumor Targeting Therapy and Selective Killing)
View Full-Text   |   Download PDF [2963 KB, uploaded 27 December 2016]   |  

Abstract

Colorectal cancer is the third most common cancer worldwide. Aberrant overexpression of antiapoptotic BCL-2 (B-cell lymphoma 2) family proteins is closely linked to tumorigenesis and poor prognosis in colorectal cancer. Obatoclax is an inhibitor targeting all antiapoptotic BCL-2 proteins. A previous study has described the antiproliferative action of obatoclax in one human colorectal cancer cell line without elucidating the underlying mechanisms. We herein reported that, in a panel of human colorectal cancer cell lines, obatoclax inhibits cell proliferation, suppresses clonogenicity, and induces G1-phase cell cycle arrest, along with cyclin D1 downregulation. Notably, ectopic cyclin D1 overexpression abrogated clonogenicity suppression but also G1-phase arrest elicited by obatoclax. Mechanistically, pre-treatment with the proteasome inhibitor MG-132 restored cyclin D1 levels in all obatoclax-treated cell lines. Cycloheximide chase analyses further revealed an evident reduction in the half-life of cyclin D1 protein by obatoclax, confirming that obatoclax downregulates cyclin D1 through induction of cyclin D1 proteasomal degradation. Lastly, threonine 286 phosphorylation of cyclin D1, which is essential for initiating cyclin D1 proteasomal degradation, was induced by obatoclax in one cell line but not others. Collectively, we reveal a novel anticancer mechanism of obatoclax by validating that obatoclax targets cyclin D1 for proteasomal degradation to downregulate cyclin D1 for inducing antiproliferation. View Full-Text
Keywords: obatoclax; BH3 (BCL-2 homology 3) mimetics; cyclin D1; proteasomal degradation; G1-phase arrest; antiproliferation; colorectal cancer obatoclax; BH3 (BCL-2 homology 3) mimetics; cyclin D1; proteasomal degradation; G1-phase arrest; antiproliferation; colorectal cancer
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MDPI and ACS Style

Or, C.-H.R.; Chang, Y.; Lin, W.-C.; Lee, W.-C.; Su, H.-L.; Cheung, M.-W.; Huang, C.-P.; Ho, C.; Chang, C.-C. Obatoclax, a Pan-BCL-2 Inhibitor, Targets Cyclin D1 for Degradation to Induce Antiproliferation in Human Colorectal Carcinoma Cells. Int. J. Mol. Sci. 2017, 18, 44.

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