title: Activation of p53 with ilimaquinone and ethylsmenoquinone, marine sponge metabolites, induces apoptosis and autophagy in colon cancer cells.
abstract: The tumor suppressor, p53, plays an essential role in the cellular response to stress through regulating the expression of genes involved in cell cycle arrest, apoptosis and autophagy. Here, we used a cell-based reporter system for the detection of p53 response transcription to identify the marine sponge metabolites, ilimaquinone and ethylsmenoquinone, as activators of the p53 pathway. We demonstrated that ilimaquinone and ethylsmenoquinone efficiently stabilize the p53 protein through promotion of p53 phosphorylation at Ser15 in both HCT116 and RKO colon cancer cells. Moreover, both compounds upregulate the expression of p21WAF1/CIP1, a p53-dependent gene, and suppress proliferation of colon cancer cells. In addition, ilimaquinone and ethylsmenoquinone induced G2/M cell cycle arrest and increased caspase-3 cleavage and the population of cells that positively stained with Annexin V-FITC, both of which are typical biochemical markers of apoptosis. Furthermore, autophagy was elicited by both compounds, as indicated by microtubule-associated protein 1 light chain 3 (LC3) puncta formations and LC3-II turnover in HCT116 cells. Our findings suggest that ilimaquinone and ethylsmenoquinone exert their anti-cancer activity by activation of the p53 pathway and may have significant potential as chemo-preventive and therapeutic agents for human colon cancer.
authors.affiliation: Department of Bio and Fermentation Convergence Technology, Kookmin University, Seoul 136-702, Korea. IHyunYoungg@gmail.com.
authors.forename: Hyun-Young
authors.initials: HY
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Chungnam national University, 305-764 Daejeon, Korea. doccap@naver.com.
authors.forename: Kyu Jin
authors.initials: KJ
authors.lastname: Chung
authors.affiliation: Department of Chemistry, University of Iowa, Iowa City, IA 52242, USA. inhyun-hwang@uiowa.edu.
authors.forename: In Hyun
authors.initials: IH
authors.lastname: Hwang
authors.affiliation: Department of Life Science, Sogang University, Seoul 121-742, Korea. dmulder@dreamwiz.com.
authors.forename: Jungsuk
authors.initials: J
authors.lastname: Gwak
authors.affiliation: Department of Bio and Fermentation Convergence Technology, Kookmin University, Seoul 136-702, Korea. qkr092@nate.com.
authors.forename: Seoyoung
authors.initials: S
authors.lastname: Park
authors.affiliation: Department of Life Science, Sogang University, Seoul 121-742, Korea. bgju@sogang.ac.kr.
authors.forename: Bong Gun
authors.initials: BG
authors.lastname: Ju
authors.affiliation: College of Pharmacy, Chungnam national University, 305-764 Daejeon, Korea. yunej@cnu.ac.kr.
authors.forename: Eunju
authors.initials: E
authors.lastname: Yun
authors.affiliation: Department of Bioscience and Biotechnology, Konkuk University, Seoul 143-701, Korea. kimde@konkuk.ac.kr.
authors.forename: Dong-Eun
authors.initials: DE
authors.lastname: Kim
authors.affiliation: BK21+, Department of Cogno-Mechatronics Engineering, Pusan National University, Busan 609-735, Korea. younghc@pusan.ac.kr.
authors.forename: Young-Hwa
authors.initials: YH
authors.lastname: Chung
authors.affiliation: College of Pharmacy, Chungnam national University, 305-764 Daejeon, Korea.
authors.forename: MinKyun
authors.initials: M
authors.lastname: Na
authors.affiliation: College of Pharmacy, Chungnam national University, 305-764 Daejeon, Korea.
authors.forename: Gyu-Yong
authors.initials: GY
authors.lastname: Song
authors.affiliation: Department of Bio and Fermentation Convergence Technology, Kookmin University, Seoul 136-702, Korea. ohsa@kookmin.ac.kr.
authors.forename: Sangtaek
authors.initials: S
authors.lastname: Oh
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D016227:Benzoquinones / Q000494:pharmacology*; D045744:Cell Line, Tumor / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy; D016195:G2 Phase / Q000187:drug effects; D045325:HCT116 Cells / Q000187:drug effects*; D006801:Humans; D011809:Quinones / Q000494:pharmacology*; D012717:Sesquiterpenes / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones; D011809:Quinones; D012717:Sesquiterpenes; D016159:Tumor Suppressor Protein p53; C000594479:ethylsmenoquinone; C467077:ilimaquinone