PMID- 31638203
OWN - NLM
STAT- MEDLINE
DCOM- 20200402
LR  - 20200402
IS  - 1791-2423 (Electronic)
IS  - 1019-6439 (Linking)
VI  - 55
IP  - 6
DP  - 2019 Dec
TI  - Tumor necrosis factor-alpha triggers opposing signals in head and neck squamous cell 
      carcinoma and induces apoptosis via mitochondrial- and 
      non-mitochondrial-dependent pathways.
PG  - 1324-1338
LID - 10.3892/ijo.2019.4900 [doi]
AB  - Head and neck squamous cell carcinoma (HNSCC) remains one of the most common 
      malignancies worldwide. Although the treatment outcomes of HNSCC have improved in 
      recent years, the prognosis of patients with advanced-stage disease remains poor. 
      Current treatment strategies for HNSCC include surgery as a primary therapy, 
      while radio-, chemo-, and biotherapeutics can be applied as second-line therapy. 
      Although tumor necrosis factor-alpha (TNF-alpha) is a potent tumor suppressor cytokine, 
      the stimulation of opposing signals impairs its clinical utility as an anticancer 
      agent. The aim of this study was to elucidate the mechanisms regulating 
      TNF-alpha‑induced opposing signals and their biological consequences in HNSCC cell 
      lines. We determined the molecular mechanisms of TNF-alpha-induced opposing signals 
      in HNSCC cells. Our in vitro analysis indicated that one of these signals 
      triggers apoptosis, while the other induces both apoptosis and cell survival. The 
      TNF-alpha-induced survival of HNSCC cells is mediated by the TNF receptor-associated 
      factor 2 (TRAF2)/nuclear factor (NF)-kappaB-dependent pathway, while TNF-alpha-induced 
      apoptosis is mediated by mitochondrial and non-mitochondrial-dependent mechanisms 
      through FADD-caspase-8-caspase-3 and ASK-JNK-p53-Noxa pathways. The localization 
      of Noxa protein to both the mitochondria and endoplasmic reticulum (ER) was found 
      to cause mitochondrial dysregulation and ER stress, respectively. Using 
      inhibitory experiments, we demonstrated that the FADD‑caspase-8‑caspase-3 
      pathway, together with mitochondrial dysregulation and ER stress-dependent 
      pathways, are essential for the modulation of apoptosis, and the NF-kappaB pathway is 
      essential for the modulation of anti-apoptotic effects/cell survival during the 
      exposure of HNSCC cells to TNF-alpha. Our data provide insight into the mechanisms of 
      TNF-alpha-induced opposing signals in HNSCC cells and may further help in the 
      development of novel therapeutic approaches with which to minimize the systemic 
      toxicity of TNF-alpha.
FAU - Selimovic, Denis
AU  - Selimovic D
AD  - INSERM UMR 1121, University of Strasbourg, 67000 Strasbourg, France.
FAU - Wahl, Renate U
AU  - Wahl RU
AD  - Clinic of Dermatology, University Hospital omicronf Aachen, 52074 Aachen, Germany.
FAU - Ruiz, Emmanuelle
AU  - Ruiz E
AD  - Department of Surgery, Tulane University School of Medicine, New Orleans, LA 
      70112, USA.
FAU - Aslam, Rizwan
AU  - Aslam R
AD  - Department of Otolaryngology, Tulane University School of Medicine, New Orleans, 
      LA 70112, USA.
FAU - Flanagan, Thomas W
AU  - Flanagan TW
AD  - Department of Pharmacology and Experimental Therapeutics, LSU Health Sciences 
      Center, New Orleans, LA 70112, USA.
FAU - Hassan, Sofie-Yasmin
AU  - Hassan SY
AD  - Clinic of Dermatology, University Hospital omicronf Aachen, 52074 Aachen, Germany.
FAU - Santourlidis, Simeon
AU  - Santourlidis S
AD  - Epigenetics Core Laboratory, Institute of Transplantation Diagnostics and Cell 
      Therapeutics, University Hospital of Dusseldorf, Heinrich-Heine-University of 
      Dusseldorf, 40225 Dusseldorf, Germany.
FAU - Haikel, Youssef
AU  - Haikel Y
AD  - INSERM UMR 1121, University of Strasbourg, 67000 Strasbourg, France.
FAU - Friedlander, Paul
AU  - Friedlander P
AD  - Department of Otolaryngology, Tulane University School of Medicine, New Orleans, 
      LA 70112, USA.
FAU - Megahed, Mosaad
AU  - Megahed M
AD  - Clinic of Dermatology, University Hospital omicronf Aachen, 52074 Aachen, Germany.
FAU - Kandil, Emad
AU  - Kandil E
AD  - Department of Surgery, Tulane University School of Medicine, New Orleans, LA 
      70112, USA.
FAU - Hassan, Mohamed
AU  - Hassan M
AD  - INSERM UMR 1121, University of Strasbourg, 67000 Strasbourg, France.
LA  - eng
PT  - Journal Article
DEP - 20191017
PL  - Greece
TA  - Int J Oncol
JT  - International journal of oncology
JID - 9306042
RN  - 0 (PSMD2 protein, human)
RN  - 0 (TNF Receptor-Associated Factor 2)
SB  - IM
MH  - Apoptosis/*genetics
MH  - Cell Line, Tumor
MH  - Cell Survival/genetics
MH  - Endoplasmic Reticulum Stress/genetics
MH  - *Gene Expression Regulation, Neoplastic
MH  - Head and Neck Neoplasms/*genetics/pathology
MH  - Humans
MH  - Mitochondria/genetics/metabolism
MH  - Signal Transduction/genetics
MH  - Squamous Cell Carcinoma of Head and Neck/*genetics/pathology
MH  - TNF Receptor-Associated Factor 2/*metabolism
EDAT- 2019/10/23 06:00
MHDA- 2020/04/03 06:00
CRDT- 2019/10/23 06:00
PHST- 2017/11/07 00:00 [received]
PHST- 2018/02/21 00:00 [accepted]
PHST- 2019/10/23 06:00 [pubmed]
PHST- 2020/04/03 06:00 [medline]
PHST- 2019/10/23 06:00 [entrez]
AID - 10.3892/ijo.2019.4900 [doi]
PST - ppublish
SO  - Int J Oncol. 2019 Dec;55(6):1324-1338. doi: 10.3892/ijo.2019.4900. Epub 2019 Oct 
      17.