title: Antitumor effects of a sirtuin inhibitor, tenovin-6, against gastric cancer cells via death receptor 5 up-regulation.
abstract: Up-regulated sirtuin 1 (SIRT1), an NAD+-dependent class III histone deacetylase, deacetylates p53 and inhibits its transcriptional activity, leading to cell survival. SIRT1 overexpression has been reported to predict poor survival in some malignancies, including gastric cancer. However, the antitumor effect of SIRT1 inhibition remains elusive in gastric cancer. Here, we investigated the antitumor mechanisms of a sirtuin inhibitor, tenovin-6, in seven human gastric cancer cell lines (four cell lines with wild-type TP53, two with mutant-type TP53, and one with null TP53). Interestingly, tenovin-6 induced apoptosis in all cell lines, not only those with wild-type TP53, but also mutant-type and null versions, accompanied by up-regulation of death receptor 5 (DR5). In the KatoIII cell line (TP53-null), DR5 silencing markedly attenuated tenovin-6-induced apoptosis, suggesting that the pivotal mechanism behind its antitumor effects is based on activation of the death receptor signal pathway. Although endoplasmic reticulum stress caused by sirtuin inhibitors was reported to induce DR5 up-regulation in other cancer cell lines, we could not find marked activation of its related molecules, such as ATF6, PERK, and CHOP, in gastric cancer cells treated with tenovin-6. Tenovin-6 in combination with docetaxel or SN-38 exerted a slight to moderate synergistic cytotoxicity against gastric cancer cells. In conclusion, tenovin-6 has potent antitumor activity against human gastric cancer cells via DR5 up-regulation. Our results should be helpful for the future clinical development of sirtuin inhibitors.
authors.affiliation: Department of Gastroenterology, Institute of Clinical Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Hirai
authors.affiliation: Department of Gastroenterology, Institute of Clinical Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Endo
authors.affiliation: Department of Gastroenterology, Institute of Clinical Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Rie
authors.initials: R
authors.lastname: Saito
authors.affiliation: Department of Gastroenterology, Institute of Clinical Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Hirose
authors.affiliation: Department of Gastroenterology, Institute of Clinical Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Takunori
authors.initials: T
authors.lastname: Ueno
authors.affiliation: Department of Gastroenterology, Institute of Clinical Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Suzuki
authors.affiliation: Department of Gastroenterology, Institute of Clinical Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Yamato
authors.affiliation: Department of Gastroenterology, Institute of Clinical Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Abei
authors.affiliation: Department of Gastroenterology, Institute of Clinical Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Ichinosuke
authors.initials: I
authors.lastname: Hyodo
mesh_terms: D051702:Activating Transcription Factor 6 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology*; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D000077143:Docetaxel; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D000077146:Irinotecan; D061986:MCF-7 Cells; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors*; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D043823:Taxoids / Q000494:pharmacology; D051742:Transcription Factor CHOP / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects*; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: C497111:ATF6 protein, human; D051702:Activating Transcription Factor 6; D000970:Antineoplastic Agents; D001549:Benzamides; C497249:DDIT3 protein, human; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C495901:TP53 protein, human; D043823:Taxoids; D016159:Tumor Suppressor Protein p53; C574854:tenovin-6; D051742:Transcription Factor CHOP; D000077143:Docetaxel; D000077146:Irinotecan; C460640:EIF2AK3 protein, human; D019892:eIF-2 Kinase; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D002166:Camptothecin