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Mar. Drugs 2015, 13(3), 1340-1359; doi:10.3390/md13031340

The Anticancer Effect of (1S,2S,3E,7E,11E)-3,7,11, 15-Cembratetraen-17,2-olide(LS-1) through the Activation of TGF-β Signaling in SNU-C5/5-FU, Fluorouracil-Resistant Human Colon Cancer Cells

1
Department of Medicine, School of Medicine, Institute of Medical Sciences, Jeju National University, 102 Jejudaehakno, Jeju 690-756, Korea
2
College of Pharmacy, Chungnam National University, Daejeon 305-764, Korea
3
Research Center for Resistant Cells and Department of Pharmacology, College of Medicine, Chosun University, Seosuk-dong, Dong-gu, Gwangju 501-759, Korea
*
Author to whom correspondence should be addressed.
Academic Editor: Sergey A. Dyshlovoy
Received: 25 November 2014 / Revised: 3 March 2015 / Accepted: 4 March 2015 / Published: 16 March 2015
(This article belongs to the Collection Marine Compounds and Cancer)
View Full-Text   |   Download PDF [861 KB, uploaded 16 March 2015]   |  

Abstract

The anticancer effect of (1S,2S,3E,7E,11E)-3,7,11,15-cembratetraen-17,2-olide (LS-1) from Lobophytum sp. has been already reported in HT-29 human colorectal cancer cells. In this study, we examined the effect of LS-1 on the apoptosis induction of SNU-C5/5-FU, fluorouracil-resistant human colon cancer cells. Furthermore, we investigated whether the apoptosis-induction effect of LS-1 could arise from the activation of the TGF-β pathway. In SNU-C5/5-FU treated with LS-1 of 7.1 μM (IC50), we could observe the various apoptotic characteristics, such as the increase of apoptotic bodies, the increase of the sub-G1 hypodiploid cell population, the decrease of the Bcl-2 level, the increase of procaspase-9 cleavage, the increase of procaspase-3 cleavage and the increase of poly(ADP-ribose) polymerase cleavage. Interestingly, the apoptosis-induction effect of LS-1 was also accompanied by the increase of Smad-3 phosphorylation and the downregulation of c-Myc in SNU-C5/5-FU. LS-1 also increased the nuclear localization of phospho-Smad-3 and Smad-4. We examined whether LS-1 could downregulate the expression of carcinoembryonic antigen (CEA), a direct inhibitor of TGF-β signaling. LS-1 decreased the CEA level, as well as the direct interaction between CEA and TGF-βR1 in the apoptosis-induction condition of SNU-C5/5-FU. To examine whether LS-1 can induce apoptosis via the activation of TGF-β signaling, the SNU-C5/5-FU cells were treated with LS-1 in the presence or absence of SB525334, a TGF-βRI kinase inhibitor. SB525334 inhibited the effect of LS-1 on the apoptosis induction. These findings provide evidence demonstrating that the apoptosis-induction effect of LS-1 results from the activation of the TGF-β pathway via the downregulation of CEA in SNU-C5/5-FU. View Full-Text
Keywords: LS-1; SNU-C5/5-FU; apoptosis; TGF-β signaling; carcinoembryonic antigen LS-1; SNU-C5/5-FU; apoptosis; TGF-β signaling; carcinoembryonic antigen
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Kim, E.-J.; Kang, J.-I.; Kwak, J.-W.; Jeon, C.-H.; Tung, N.-H.; Kim, Y.-H.; Choi, C.-H.; Hyun, J.-W.; Koh, Y.-S.; Yoo, E.-S.; Kang, H.-K. The Anticancer Effect of (1S,2S,3E,7E,11E)-3,7,11, 15-Cembratetraen-17,2-olide(LS-1) through the Activation of TGF-β Signaling in SNU-C5/5-FU, Fluorouracil-Resistant Human Colon Cancer Cells. Mar. Drugs 2015, 13, 1340-1359.

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