PMID- 29328423
OWN - NLM
STAT- MEDLINE
DCOM- 20180814
LR  - 20211022
IS  - 1791-3004 (Electronic)
IS  - 1791-2997 (Linking)
VI  - 17
IP  - 3
DP  - 2018 Mar
TI  - Cetuximab enhances cisplatin-induced endoplasmic reticulum stress-associated 
      apoptosis in laryngeal squamous cell carcinoma cells by inhibiting expression of 
      TXNDC5.
PG  - 4767-4776
LID - 10.3892/mmr.2018.8376 [doi]
AB  - Cisplatin and cetuximab, an anti‑epidermal growth factor receptor (EGFR) 
      monoclonal humanized antibody, have been used for treatment of laryngeal squamous 
      cell carcinoma (LSCC). It has been demonstrated that cisplatin and inhibition of 
      EGFR signaling may induce endoplasmic reticulum (ER) stress‑associated apoptosis. 
      However, ER protein thioredoxin domain‑containing protein 5 (TXNDC5) reportedly 
      protects cells from ER stress‑associated apoptosis. The present study 
      investigated the interaction between cisplatin, cetuximab and TXNDC5 on ER 
      stress‑associated apoptosis in LSCC cells. AMC‑HN‑8 human LSCC cells with or 
      without TXNDC5 overexpression or knockdown were treated with cisplatin (5, 10, 20 
      and 40 microM) and/or cetuximab (10, 50, 100 and 150 microg/ml), for 12, 24, 36 and 48 h. 
      Cisplatin and cetuximab concentration‑ and time‑dependently increased and 
      decreased the expression of TXNDC5 in AMC‑HN‑8 cells, respectively. Knockdown of 
      TXNDC5 markedly augmented cisplatin‑induced levels of CCAAT/enhancer‑binding 
      protein homologous protein (CHOP), caspase‑3 activity and apoptosis; while 
      overexpression of TXNDC5 largely eliminated cetuximab‑induced levels of CHOP, 
      caspase‑3 activity and apoptosis. Cisplatin and cetuximab demonstrated a 
      combinatorial effect on increasing the levels of CHOP, caspase‑3 activity and 
      apoptosis, which was largely eliminated by overexpression of TXNDC5 or a reactive 
      oxygen species (ROS) scavenger/antagonist. In addition, promoter/luciferase 
      reporter assays revealed that cisplatin and cetuximab regulated the expression of 
      TXNDC5 at the gene transcription/promoter level. In conclusion, the findings 
      suggested that ER stress‑associated apoptosis is a major mechanism underlying the 
      apoptotic effect of cisplatin and cetuximab on LSCC cells; cetuximab enhanced 
      cisplatin‑induced ER stress‑associated apoptosis in LSCC cells largely by 
      inhibiting the expression of TXNDC5 and thereby increasing ROS production; 
      cisplatin and cetuximab had stimulatory and inhibitory effects on the TXNDC5 gene 
      promoter, respectively. The present study offered novel insights into the 
      pharmacological effects of cisplatin and cetuximab on LSCC. It also suggested 
      that TXNDC5 may be a potential therapeutic target for LSCC.
FAU - Peng, Fusen
AU  - Peng F
AD  - Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central 
      South University, Changsha, Hunan 410008, P.R. China.
FAU - Zhang, Hailin
AU  - Zhang H
AD  - Department of Head and Neck Surgery, Hunan Tumor Hospital, Changsha, Hunan 
      410013, P.R. China.
FAU - Du, Youhong
AU  - Du Y
AD  - Department of Otolaryngology Head and Neck Surgery, Loudi Central Hospital, 
      Loudi, Hunan 417000, P.R. China.
FAU - Tan, Pingqing
AU  - Tan P
AD  - Department of Head and Neck Surgery, Hunan Tumor Hospital, Changsha, Hunan 
      410013, P.R. China.
LA  - eng
PT  - Journal Article
DEP - 20180105
PL  - Greece
TA  - Mol Med Rep
JT  - Molecular medicine reports
JID - 101475259
RN  - 0 (Antineoplastic Agents, Immunological)
RN  - 0 (DDIT3 protein, human)
RN  - 0 (Histones)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Reactive Oxygen Species)
RN  - 147336-12-7 (Transcription Factor CHOP)
RN  - EC 3.4.22.- (Caspase 3)
RN  - EC 5.3.4.1 (Protein Disulfide-Isomerases)
RN  - EC 5.3.4.1 (TXNDC5 protein, human)
RN  - PQX0D8J21J (Cetuximab)
RN  - Q20Q21Q62J (Cisplatin)
SB  - IM
MH  - Antineoplastic Agents, Immunological/*pharmacology
MH  - Apoptosis/*drug effects
MH  - Carcinoma, Squamous Cell/metabolism/pathology
MH  - Caspase 3/metabolism
MH  - Cell Line, Tumor
MH  - Cetuximab/*pharmacology
MH  - Cisplatin/pharmacology
MH  - Endoplasmic Reticulum Stress/*drug effects
MH  - Histones/metabolism
MH  - Humans
MH  - Laryngeal Neoplasms/metabolism/pathology
MH  - Promoter Regions, Genetic
MH  - Protein Disulfide-Isomerases/antagonists & inhibitors/genetics/*metabolism
MH  - RNA Interference
MH  - RNA, Small Interfering/metabolism
MH  - Reactive Oxygen Species/metabolism
MH  - Transcription Factor CHOP/metabolism
OTO - NOTNLM
OT  - cetuximab
OT  - cisplatin
OT  - laryngeal squamous cell carcinoma
OT  - endoplasmic reticulum stress
OT  - thioredoxin domain-containing protein 5
OT  - apoptosis
EDAT- 2018/01/13 06:00
MHDA- 2018/08/15 06:00
CRDT- 2018/01/13 06:00
PHST- 2016/05/26 00:00 [received]
PHST- 2017/04/13 00:00 [accepted]
PHST- 2018/01/13 06:00 [pubmed]
PHST- 2018/08/15 06:00 [medline]
PHST- 2018/01/13 06:00 [entrez]
AID - 10.3892/mmr.2018.8376 [doi]
PST - ppublish
SO  - Mol Med Rep. 2018 Mar;17(3):4767-4776. doi: 10.3892/mmr.2018.8376. Epub 2018 Jan 
      5.