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

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

  • Int J Mol Sci. 2016 Dec 27;18(1):44. doi: 10.3390/ijms18010044.
Chi-Hung R Or 1 2,  Yachu Chang 3,  Wei-Cheng Lin 4,  Wee-Chyan Lee 5,  Hong-Lin Su 6 7 8 9,  Muk-Wing Cheung 10,  Chang-Po Huang 11,  Cheesang Ho 12,  Chia-Che Chang 13 14 15 16 17 18 19
Affiliations

Affiliations

  • 1 Department of Life Science, National Chung Hsing University, 145 Xingda Road, Taichung 40227, Taiwan. [email protected].
  • 2 Department of Anesthesiology, Kuang Tien General Hospital, Dajia Branch, 321 Jingguo Road, Taichung 43761, Taiwan. [email protected].
  • 3 Institute of Biomedical Sciences, National Chung Hsing University, 145 Xingda Road, Taichung 40227, Taiwan. [email protected].
  • 4 Institute of Biomedical Sciences, National Chung Hsing University, 145 Xingda Road, Taichung 40227, Taiwan. [email protected].
  • 5 Institute of Biomedical Sciences, National Chung Hsing University, 145 Xingda Road, Taichung 40227, Taiwan. [email protected].
  • 6 Department of Life Science, National Chung Hsing University, 145 Xingda Road, Taichung 40227, Taiwan. [email protected].
  • 7 Ph.D. Program in Translational Medicine, National Chung Hsing University, 145 Xingda Road, Taichung 40227, Taiwan. [email protected].
  • 8 Agricultural Biotechnology Center, National Chung Hsing University, 145 Xingda Road, Taichung 40227, Taiwan. [email protected].
  • 9 Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, 145 Xingda Road, Taichung 40227, Taiwan. [email protected].
  • 10 Department of Anesthesiology, Kuang Tien General Hospital, Dajia Branch, 321 Jingguo Road, Taichung 43761, Taiwan. [email protected].
  • 11 Department of Anesthesiology, Kuang Tien General Hospital, Dajia Branch, 321 Jingguo Road, Taichung 43761, Taiwan. [email protected].
  • 12 Department of Anesthesiology, Kuang Tien General Hospital, Dajia Branch, 321 Jingguo Road, Taichung 43761, Taiwan. [email protected].
  • 13 Institute of Biomedical Sciences, National Chung Hsing University, 145 Xingda Road, Taichung 40227, Taiwan. [email protected].
  • 14 Department of Life Science, National Chung Hsing University, 145 Xingda Road, Taichung 40227, Taiwan. [email protected].
  • 15 Ph.D. Program in Translational Medicine, National Chung Hsing University, 145 Xingda Road, Taichung 40227, Taiwan. [email protected].
  • 16 Agricultural Biotechnology Center, National Chung Hsing University, 145 Xingda Road, Taichung 40227, Taiwan. [email protected].
  • 17 Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, 145 Xingda Road, Taichung 40227, Taiwan. [email protected].
  • 18 Department of Medical Research, China Medical University Hospital, 2 Yude Road, Taichung 40447, Taiwan. [email protected].
  • 19 Department of Biotechnology, Asia University, 500 Liufeng Road, Taichung 41354, Taiwan. [email protected].
PMID: 28035994 DOI: 10.3390/ijms18010044
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

BH3 (BCL-2 homology 3) mimetics; G1-phase arrest; antiproliferation; colorectal cancer; cyclin D1; obatoclax; proteasomal degradation.

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