title: 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.
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.
authors.affiliation: Department of Medicine, School of Medicine, Institute of Medical Sciences, Jeju National University, 102 Jejudaehakno, Jeju 690-756, Korea. ejk8730@naver.com.
authors.forename: Eun-Ji
authors.initials: EJ
authors.lastname: Kim
authors.affiliation: Department of Medicine, School of Medicine, Institute of Medical Sciences, Jeju National University, 102 Jejudaehakno, Jeju 690-756, Korea. jejumed15@naver.com.
authors.forename: Jung-Il
authors.initials: JI
authors.lastname: Kang
authors.affiliation: Department of Medicine, School of Medicine, Institute of Medical Sciences, Jeju National University, 102 Jejudaehakno, Jeju 690-756, Korea. jejumed15@naver.com.
authors.forename: Jeon-Won
authors.initials: JW
authors.lastname: Kwak
authors.affiliation: Department of Medicine, School of Medicine, Institute of Medical Sciences, Jeju National University, 102 Jejudaehakno, Jeju 690-756, Korea. katastrope@naver.com.
authors.forename: Chan-Hee
authors.initials: CH
authors.lastname: Jeon
authors.affiliation: College of Pharmacy, Chungnam National University, Daejeon 305-764, Korea. tunginpc@gmail.com.
authors.forename: Nguyen-Huu
authors.initials: NH
authors.lastname: Tung
authors.affiliation: College of Pharmacy, Chungnam National University, Daejeon 305-764, Korea. yhk@cnu.ac.kr.
authors.forename: Young-Ho
authors.initials: YH
authors.lastname: Kim
authors.affiliation: Research Center for Resistant Cells and Department of Pharmacology, College of Medicine, Chosun University, Seosuk-dong, Dong-gu, Gwangju 501-759, Korea. chchoi@chosun.ac.kr.
authors.forename: Cheol-Hee
authors.initials: CH
authors.lastname: Choi
authors.affiliation: Department of Medicine, School of Medicine, Institute of Medical Sciences, Jeju National University, 102 Jejudaehakno, Jeju 690-756, Korea. jinwonh@jejunu.ac.kr.
authors.forename: Jin-Won
authors.initials: JW
authors.lastname: Hyun
authors.affiliation: Department of Medicine, School of Medicine, Institute of Medical Sciences, Jeju National University, 102 Jejudaehakno, Jeju 690-756, Korea. yskoh7@jejunu.ac.kr.
authors.forename: Young-Sang
authors.initials: YS
authors.lastname: Koh
authors.affiliation: Department of Medicine, School of Medicine, Institute of Medical Sciences, Jeju National University, 102 Jejudaehakno, Jeju 690-756, Korea. eunsyoo@jejunu.ac.kr.
authors.forename: Eun-Sook
authors.initials: ES
authors.lastname: Yoo
authors.affiliation: Department of Medicine, School of Medicine, Institute of Medical Sciences, Jeju National University, 102 Jejudaehakno, Jeju 690-756, Korea. pharmkhk@jejunu.ac.kr.
authors.forename: Hee-Kyoung
authors.initials: HK
authors.lastname: Kang
mesh_terms: D000818:Animals; D037421:Anthozoa / Q000737:chemistry; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000302:isolation & purification / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy*; D004224:Diterpenes / Q000008:administration & dosage / Q000302:isolation & purification / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005472:Fluorouracil / Q000494:pharmacology; D019073:HT29 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: C576714:(1S,2S,3E,7E,11E)-3,7,11,15-cembratetraen-17,2-olide; D000970:Antineoplastic Agents; D004224:Diterpenes; D016212:Transforming Growth Factor beta; D005472:Fluorouracil