Obatoclax, a pan-BCL-2 Inhibitor, targets Cyclin D1 for degradation to induce antiproliferation in human colorectal carcinoma cells

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Title:	Obatoclax, a pan-BCL-2 Inhibitor, targets Cyclin D1 for degradation to induce antiproliferation in human colorectal carcinoma cells
Authors:	Chang, 柯子鴻；Chi-Hung R. Or；Yachu Chang；Yachu Chang；Wei-Cheng Li；Wei-Cheng Lin；Wee-Chyan Le；Wee-Chyan Lee；Hong-Lin Su；Hong-Lin Su；Muk-Wing Che；Muk-Wing Cheung；Chang-Po Hua；Chang-Po Huang；Cheesang Ho；Cheesang Ho；張嘉哲；Chia-Che
Contributors:	生物科技學系
Date:	2017-01
Issue Date:	2017-10-30 02:44:39 (UTC+0)
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. Keywords: obatoclax, BH3 (BCL-2 homology 3) mimetics, cyclin D1, proteasomal degradation, G1-phase arrest, antiproliferation, colorectal cancer
Relation:	INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Appears in Collections:	[生物科技學系] 期刊論文

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