Antitumor effects of a sirtuin inhibitor, tenovin-6, against gastric cancer cells via death receptor 5 up-regulation.
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 antitumo...
Main Authors: | , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Public Library of Science (PLoS)
2014-01-01
|
Series: | PLoS ONE |
Online Access: | http://europepmc.org/articles/PMC4102575?pdf=render |
id |
doaj-05397061318642f19ae9674c378b852a |
---|---|
record_format |
Article |
spelling |
doaj-05397061318642f19ae9674c378b852a2020-11-25T01:46:28ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0197e10283110.1371/journal.pone.0102831Antitumor effects of a sirtuin inhibitor, tenovin-6, against gastric cancer cells via death receptor 5 up-regulation.Sachiko HiraiShinji EndoRie SaitoMitsuaki HiroseTakunori UenoHideo SuzukiKenji YamatoMasato AbeiIchinosuke HyodoUp-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.http://europepmc.org/articles/PMC4102575?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Sachiko Hirai Shinji Endo Rie Saito Mitsuaki Hirose Takunori Ueno Hideo Suzuki Kenji Yamato Masato Abei Ichinosuke Hyodo |
spellingShingle |
Sachiko Hirai Shinji Endo Rie Saito Mitsuaki Hirose Takunori Ueno Hideo Suzuki Kenji Yamato Masato Abei Ichinosuke Hyodo Antitumor effects of a sirtuin inhibitor, tenovin-6, against gastric cancer cells via death receptor 5 up-regulation. PLoS ONE |
author_facet |
Sachiko Hirai Shinji Endo Rie Saito Mitsuaki Hirose Takunori Ueno Hideo Suzuki Kenji Yamato Masato Abei Ichinosuke Hyodo |
author_sort |
Sachiko Hirai |
title |
Antitumor effects of a sirtuin inhibitor, tenovin-6, against gastric cancer cells via death receptor 5 up-regulation. |
title_short |
Antitumor effects of a sirtuin inhibitor, tenovin-6, against gastric cancer cells via death receptor 5 up-regulation. |
title_full |
Antitumor effects of a sirtuin inhibitor, tenovin-6, against gastric cancer cells via death receptor 5 up-regulation. |
title_fullStr |
Antitumor effects of a sirtuin inhibitor, tenovin-6, against gastric cancer cells via death receptor 5 up-regulation. |
title_full_unstemmed |
Antitumor effects of a sirtuin inhibitor, tenovin-6, against gastric cancer cells via death receptor 5 up-regulation. |
title_sort |
antitumor effects of a sirtuin inhibitor, tenovin-6, against gastric cancer cells via death receptor 5 up-regulation. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2014-01-01 |
description |
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. |
url |
http://europepmc.org/articles/PMC4102575?pdf=render |
work_keys_str_mv |
AT sachikohirai antitumoreffectsofasirtuininhibitortenovin6againstgastriccancercellsviadeathreceptor5upregulation AT shinjiendo antitumoreffectsofasirtuininhibitortenovin6againstgastriccancercellsviadeathreceptor5upregulation AT riesaito antitumoreffectsofasirtuininhibitortenovin6againstgastriccancercellsviadeathreceptor5upregulation AT mitsuakihirose antitumoreffectsofasirtuininhibitortenovin6againstgastriccancercellsviadeathreceptor5upregulation AT takunoriueno antitumoreffectsofasirtuininhibitortenovin6againstgastriccancercellsviadeathreceptor5upregulation AT hideosuzuki antitumoreffectsofasirtuininhibitortenovin6againstgastriccancercellsviadeathreceptor5upregulation AT kenjiyamato antitumoreffectsofasirtuininhibitortenovin6againstgastriccancercellsviadeathreceptor5upregulation AT masatoabei antitumoreffectsofasirtuininhibitortenovin6againstgastriccancercellsviadeathreceptor5upregulation AT ichinosukehyodo antitumoreffectsofasirtuininhibitortenovin6againstgastriccancercellsviadeathreceptor5upregulation |
_version_ |
1725019314223841280 |