RRC ID 45178
Author Hirai S, Endo S, Saito R, Hirose M, Ueno T, Suzuki H, Yamato K, Abei M, Hyodo I.
Title Antitumor effects of a sirtuin inhibitor, tenovin-6, against gastric cancer cells via death receptor 5 up-regulation.
Journal PLoS ONE
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.
Volume 9(7)
Pages e102831
Published 2014
DOI 10.1371/journal.pone.0102831
PII PONE-D-13-44114
PMID 25033286
PMC PMC4102575
MeSH Activating Transcription Factor 6 / metabolism Antineoplastic Agents / pharmacology* Apoptosis / drug effects Benzamides / pharmacology* Camptothecin / analogs & derivatives Camptothecin / pharmacology Cell Line Cell Line, Tumor Docetaxel Endoplasmic Reticulum Stress / drug effects Gene Expression Regulation, Neoplastic / drug effects HEK293 Cells Humans Irinotecan MCF-7 Cells Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism* Signal Transduction / drug effects Sirtuin 1 / antagonists & inhibitors* Stomach Neoplasms / drug therapy* Stomach Neoplasms / metabolism Taxoids / pharmacology Transcription Factor CHOP / metabolism Tumor Suppressor Protein p53 / metabolism Up-Regulation / drug effects* eIF-2 Kinase / metabolism
IF 2.776
Times Cited 20
Human and Animal Cells