Suppression of TG-interacting factor sensitizes arsenic trioxide-induced apoptosis in human hepatocellular carcinoma cells

Zi Miao Liu, Ta-Chien Tseng, Duang Yang Hong, Huei-Sheng Huang

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

HCC (hepatocellular carcinoma) is among the most common and lethal cancers worldwide with a poor prognosis mainly due to a high recurrence rate and chemotherapy resistance. ATO (arsenic trioxide) is a multi-target drug that has been effectively used as an anticancer drug in acute promyelocytic leukaemia. However, a Phase II trial involving patients with HCC indicates that the use of arsenic as a single agent is not effective against HCC. TGIF (TG-interacting factor) is a transcriptional co-repressor that interferes with TGF-β (transforming growth factor-β) signalling which plays a growth-inhibitory role in HCC. In the present study, we demonstrated that ATO induced hepatocellular apoptosis via TGF-β/Smad signalling and led to downstream induction of p21 WAF1/CIP1 (p21). However, ATO could also induce TGIF expression via a post-transcriptional regulation mechanism to antagonize this effect. Using a biotin-labelled RNA probe pull-down assay and in vivo RNA immunoprecipitation analysis, we identified that HuR (human antigen R) bound to the TGIF mRNA 3′-UTR (3′-untranslated region) and prevented it from degradation. ATO treatment increased the interaction between HuR and TGIFmRNA, and reduction of HuR expression inhibited ATO-induced TGIF expression. Moreover, the EGFR (epidermal growth factor receptor)/PI3K (phosphoinositide 3-kinase)/Akt pathway was shown to mediate the post-transcriptional regulation of TGIF in response to ATO. Finally, we also demonstrated that the down-regulation of TGIF could sensitize ATO-induced HepG2 cell apoptosis. Collectively, we propose that the EGFR/PI3K/Akt pathway may regulate the post-transcriptional regulation of TGIF expression to antagonize ATO-induced apoptosis in HCC. Blockage of the PI3K/Akt pathway or TGIF expression combined with ATO treatment may be a promising strategy for HCC therapy.

Original languageEnglish
Pages (from-to)349-358
Number of pages10
JournalBiochemical Journal
Volume438
Issue number2
DOIs
Publication statusPublished - 2011 Sep 1

Fingerprint

Hepatocellular Carcinoma
Cells
Apoptosis
Phosphatidylinositol 3-Kinases
Transforming Growth Factors
Epidermal Growth Factor Receptor
Antigens
RNA Probes
arsenic trioxide
Co-Repressor Proteins
Acute Promyelocytic Leukemia
1-Phosphatidylinositol 4-Kinase
Chemotherapy
Hep G2 Cells
Arsenic
3' Untranslated Regions
Biotin
Phosphatidylinositols
Immunoprecipitation
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

@article{7a846d8cbfc54a7994316531a8658fee,
title = "Suppression of TG-interacting factor sensitizes arsenic trioxide-induced apoptosis in human hepatocellular carcinoma cells",
abstract = "HCC (hepatocellular carcinoma) is among the most common and lethal cancers worldwide with a poor prognosis mainly due to a high recurrence rate and chemotherapy resistance. ATO (arsenic trioxide) is a multi-target drug that has been effectively used as an anticancer drug in acute promyelocytic leukaemia. However, a Phase II trial involving patients with HCC indicates that the use of arsenic as a single agent is not effective against HCC. TGIF (TG-interacting factor) is a transcriptional co-repressor that interferes with TGF-β (transforming growth factor-β) signalling which plays a growth-inhibitory role in HCC. In the present study, we demonstrated that ATO induced hepatocellular apoptosis via TGF-β/Smad signalling and led to downstream induction of p21 WAF1/CIP1 (p21). However, ATO could also induce TGIF expression via a post-transcriptional regulation mechanism to antagonize this effect. Using a biotin-labelled RNA probe pull-down assay and in vivo RNA immunoprecipitation analysis, we identified that HuR (human antigen R) bound to the TGIF mRNA 3′-UTR (3′-untranslated region) and prevented it from degradation. ATO treatment increased the interaction between HuR and TGIFmRNA, and reduction of HuR expression inhibited ATO-induced TGIF expression. Moreover, the EGFR (epidermal growth factor receptor)/PI3K (phosphoinositide 3-kinase)/Akt pathway was shown to mediate the post-transcriptional regulation of TGIF in response to ATO. Finally, we also demonstrated that the down-regulation of TGIF could sensitize ATO-induced HepG2 cell apoptosis. Collectively, we propose that the EGFR/PI3K/Akt pathway may regulate the post-transcriptional regulation of TGIF expression to antagonize ATO-induced apoptosis in HCC. Blockage of the PI3K/Akt pathway or TGIF expression combined with ATO treatment may be a promising strategy for HCC therapy.",
author = "Liu, {Zi Miao} and Ta-Chien Tseng and Hong, {Duang Yang} and Huei-Sheng Huang",
year = "2011",
month = "9",
day = "1",
doi = "10.1042/BJ20101653",
language = "English",
volume = "438",
pages = "349--358",
journal = "Biochemical Journal",
issn = "0264-6021",
publisher = "Portland Press Ltd.",
number = "2",

}

Suppression of TG-interacting factor sensitizes arsenic trioxide-induced apoptosis in human hepatocellular carcinoma cells. / Liu, Zi Miao; Tseng, Ta-Chien; Hong, Duang Yang; Huang, Huei-Sheng.

In: Biochemical Journal, Vol. 438, No. 2, 01.09.2011, p. 349-358.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Suppression of TG-interacting factor sensitizes arsenic trioxide-induced apoptosis in human hepatocellular carcinoma cells

AU - Liu, Zi Miao

AU - Tseng, Ta-Chien

AU - Hong, Duang Yang

AU - Huang, Huei-Sheng

PY - 2011/9/1

Y1 - 2011/9/1

N2 - HCC (hepatocellular carcinoma) is among the most common and lethal cancers worldwide with a poor prognosis mainly due to a high recurrence rate and chemotherapy resistance. ATO (arsenic trioxide) is a multi-target drug that has been effectively used as an anticancer drug in acute promyelocytic leukaemia. However, a Phase II trial involving patients with HCC indicates that the use of arsenic as a single agent is not effective against HCC. TGIF (TG-interacting factor) is a transcriptional co-repressor that interferes with TGF-β (transforming growth factor-β) signalling which plays a growth-inhibitory role in HCC. In the present study, we demonstrated that ATO induced hepatocellular apoptosis via TGF-β/Smad signalling and led to downstream induction of p21 WAF1/CIP1 (p21). However, ATO could also induce TGIF expression via a post-transcriptional regulation mechanism to antagonize this effect. Using a biotin-labelled RNA probe pull-down assay and in vivo RNA immunoprecipitation analysis, we identified that HuR (human antigen R) bound to the TGIF mRNA 3′-UTR (3′-untranslated region) and prevented it from degradation. ATO treatment increased the interaction between HuR and TGIFmRNA, and reduction of HuR expression inhibited ATO-induced TGIF expression. Moreover, the EGFR (epidermal growth factor receptor)/PI3K (phosphoinositide 3-kinase)/Akt pathway was shown to mediate the post-transcriptional regulation of TGIF in response to ATO. Finally, we also demonstrated that the down-regulation of TGIF could sensitize ATO-induced HepG2 cell apoptosis. Collectively, we propose that the EGFR/PI3K/Akt pathway may regulate the post-transcriptional regulation of TGIF expression to antagonize ATO-induced apoptosis in HCC. Blockage of the PI3K/Akt pathway or TGIF expression combined with ATO treatment may be a promising strategy for HCC therapy.

AB - HCC (hepatocellular carcinoma) is among the most common and lethal cancers worldwide with a poor prognosis mainly due to a high recurrence rate and chemotherapy resistance. ATO (arsenic trioxide) is a multi-target drug that has been effectively used as an anticancer drug in acute promyelocytic leukaemia. However, a Phase II trial involving patients with HCC indicates that the use of arsenic as a single agent is not effective against HCC. TGIF (TG-interacting factor) is a transcriptional co-repressor that interferes with TGF-β (transforming growth factor-β) signalling which plays a growth-inhibitory role in HCC. In the present study, we demonstrated that ATO induced hepatocellular apoptosis via TGF-β/Smad signalling and led to downstream induction of p21 WAF1/CIP1 (p21). However, ATO could also induce TGIF expression via a post-transcriptional regulation mechanism to antagonize this effect. Using a biotin-labelled RNA probe pull-down assay and in vivo RNA immunoprecipitation analysis, we identified that HuR (human antigen R) bound to the TGIF mRNA 3′-UTR (3′-untranslated region) and prevented it from degradation. ATO treatment increased the interaction between HuR and TGIFmRNA, and reduction of HuR expression inhibited ATO-induced TGIF expression. Moreover, the EGFR (epidermal growth factor receptor)/PI3K (phosphoinositide 3-kinase)/Akt pathway was shown to mediate the post-transcriptional regulation of TGIF in response to ATO. Finally, we also demonstrated that the down-regulation of TGIF could sensitize ATO-induced HepG2 cell apoptosis. Collectively, we propose that the EGFR/PI3K/Akt pathway may regulate the post-transcriptional regulation of TGIF expression to antagonize ATO-induced apoptosis in HCC. Blockage of the PI3K/Akt pathway or TGIF expression combined with ATO treatment may be a promising strategy for HCC therapy.

UR - http://www.scopus.com/inward/record.url?scp=80051704370&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80051704370&partnerID=8YFLogxK

U2 - 10.1042/BJ20101653

DO - 10.1042/BJ20101653

M3 - Article

VL - 438

SP - 349

EP - 358

JO - Biochemical Journal

JF - Biochemical Journal

SN - 0264-6021

IS - 2

ER -