PMID- 23500081
OWN - NLM
STAT- MEDLINE
DCOM- 20130805
LR  - 20161126
IS  - 0006-3002 (Print)
IS  - 0006-3002 (Linking)
VI  - 1830
IP  - 6
DP  - 2013 Jun
TI  - Transcriptional and post-translational regulation of Bim is essential for TGF-beta 
      and TNF-alpha-induced apoptosis of gastric cancer cell.
PG  - 3584-92
LID - S0304-4165(13)00084-6 [pii]
LID - 10.1016/j.bbagen.2013.03.006 [doi]
AB  - BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta 
      (TGF-beta) are well known as central signaling molecules in natural antitumor 
      mechanisms. However, some cancer cells are resistant to TNF-alpha or TGF-beta-induced 
      death signaling. Herein, we investigated synergistic activities of TGF-beta and 
      TNF-alpha and molecular mechanisms involved in apoptosis of gastric cancer cells. 
      METHODS: SNU620, a human gastric carcinoma cell line was tested for cell 
      viability by treatment of TGF-beta in combination with TNF-alpha. Cell apoptosis, 
      proliferation, caspase activation and gene expression were tested using flow 
      cytometry, Western blot, MTT assay, luciferase assay and real-time qRT-PCR 
      analysis. Knockdown of target genes were performed using lentiviral shRNA system. 
      RESULTS: TGF-beta sensitizes SNU620 cells undergoing TNF-alpha-induced caspase-dependent 
      apoptosis. TNF-alpha and TGF-beta synergistically induced the degradation of 
      poly(ADP-ribose) polymerase (PARP) and caspase cascade activation. We also 
      confirmed that c-Jun NH2-terminal kinase (JNK) and Smad3 play critical roles in 
      the apoptotic pathway. In addition, a pro-apoptotic protein Bim was critical for 
      apoptosis and was regulated by TGF-beta and TNF-alpha at the transcriptional and 
      post-translational levels. Expression of Bim was induced at the transcriptional 
      level by Smad3 while Bim protein stability was maintained by a JNK-mediated 
      pathway. CONCLUSION: By understanding the synergistic activation of TGF-beta and 
      TNF-alpha in apoptosis, we may have a chance to identify good therapeutic approaches 
      for the treatment of cancers that are resistant to death signals. GENERAL 
      SIGNIFICANCE: Our results indicate that TGF-beta and TNF-alpha act in concert to 
      activate apoptosis in gastric cancer cell through crosstalk between Smad and JNK 
      signaling pathways.
CI  - Copyright (c) 2013 Elsevier B.V. All rights reserved.
FAU - Ha Thi, Huyen Trang
AU  - Ha Thi HT
AD  - Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Republic of 
      Korea.
FAU - Lim, Hee-Sun
AU  - Lim HS
FAU - Kim, Jooyoung
AU  - Kim J
FAU - Kim, Young-Mi
AU  - Kim YM
FAU - Kim, Hye-Youn
AU  - Kim HY
FAU - Hong, Suntaek
AU  - Hong S
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130315
PL  - Netherlands
TA  - Biochim Biophys Acta
JT  - Biochimica et biophysica acta
JID - 0217513
RN  - 0 (Apoptosis Regulatory Proteins)
RN  - 0 (BCL2L11 protein, human)
RN  - 0 (Bcl-2-Like Protein 11)
RN  - 0 (Membrane Proteins)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (SMAD3 protein, human)
RN  - 0 (Smad3 Protein)
RN  - 0 (Transforming Growth Factor beta)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
RN  - EC 3.4.22.- (Caspases)
SB  - IM
MH  - *Apoptosis
MH  - Apoptosis Regulatory Proteins/*biosynthesis/genetics
MH  - Bcl-2-Like Protein 11
MH  - Caspases/genetics/metabolism
MH  - Cell Line, Tumor
MH  - Female
MH  - *Gene Expression Regulation, Neoplastic
MH  - Humans
MH  - JNK Mitogen-Activated Protein Kinases/genetics/metabolism
MH  - *MAP Kinase Signaling System
MH  - Male
MH  - Membrane Proteins/*biosynthesis/genetics
MH  - Protein Stability/drug effects
MH  - Proto-Oncogene Proteins/*biosynthesis/genetics
MH  - Smad3 Protein/genetics/metabolism
MH  - Stomach Neoplasms/genetics/*metabolism/pathology
MH  - Transcription, Genetic/drug effects/genetics
MH  - Transforming Growth Factor beta/genetics/*metabolism/pharmacology
MH  - Tumor Necrosis Factor-alpha/genetics/*metabolism/pharmacology
EDAT- 2013/03/19 06:00
MHDA- 2013/08/06 06:00
CRDT- 2013/03/19 06:00
PHST- 2012/10/17 00:00 [received]
PHST- 2013/03/04 00:00 [revised]
PHST- 2013/03/07 00:00 [accepted]
PHST- 2013/03/19 06:00 [entrez]
PHST- 2013/03/19 06:00 [pubmed]
PHST- 2013/08/06 06:00 [medline]
AID - S0304-4165(13)00084-6 [pii]
AID - 10.1016/j.bbagen.2013.03.006 [doi]
PST - ppublish
SO  - Biochim Biophys Acta. 2013 Jun;1830(6):3584-92. doi: 
      10.1016/j.bbagen.2013.03.006. Epub 2013 Mar 15.