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Inhibition of GRP78 abrogates radioresistance in oropharyngeal carcinoma cells after EGFR inhibition by cetuximab.

Abstract The EGFR-specific mAb cetuximab is one of the most effective treatments for oropharyngeal carcinoma, while patient responses to EGFR inhibitors given alone are modest. Combination treatment with radiation can improve the efficacy of treatment through increasing radiosensitivity, while resistance to radiation after administration of cetuximab limits its efficiency. Radiation and drugs can damage the endoplasmic reticulum (ER) homeostatic state and result in ER stress (ERS), subsequently causing resistance to radiation and drugs. Whether the ERS pathway is involved in radioresistance after administration of cetuximab has not been reported. Herein, we show that cetuximab could increase the radiosensitivity of FaDu cells but not Detroit562 cells. In addition, cetuximab inhibited the radiation-induced activation of the ERS signalling pathway IRE1α/ATF6-GRP78 in FaDu cells, while this effect was absent in Detroit562 cells. Silencing GRP78 increased the radiosensitivity of oropharyngeal carcinoma cells and inhibited radiation-induced DNA double-strand-break (DSB) repair and autophagy. More interestingly, silencing GRP78 abrogated resistance to cetuximab and radiation in Detroit562 cells and had a synergistic effect with cetuximab in increasing the radiosensitivity of FaDu cells. Immunohistochemistry showed that overexpression of both GRP78 and EGFR was associated with a poor prognosis in oropharyngeal carcinoma patients (P<0.05). Overall, the results of this study show that radioresistance after EGFR inhibition by cetuximab is mediated by the ERS signalling pathway IRE1α/ATF6-GRP78. This suppression was consequently unable to inhibit radiation-induced DSB repair and autophagy in oropharyngeal carcinoma cells, which conferred resistance to radiotherapy and cetuximab. These results suggest that the cooperative effects of radiotherapy and cetuximab could be further improved by inhibiting GRP78 in non-responsive oropharyngeal carcinoma patients.
PMID
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Authors

Mayor MeshTerms
Keywords
Journal Title plos one
Publication Year Start




PMID- 29232380
OWN - NLM
STAT- MEDLINE
DCOM- 20180104
LR  - 20180104
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 12
IP  - 12
DP  - 2017
TI  - Inhibition of GRP78 abrogates radioresistance in oropharyngeal carcinoma cells
      after EGFR inhibition by cetuximab.
PG  - e0188932
LID - 10.1371/journal.pone.0188932 [doi]
AB  - The EGFR-specific mAb cetuximab is one of the most effective treatments for
      oropharyngeal carcinoma, while patient responses to EGFR inhibitors given alone
      are modest. Combination treatment with radiation can improve the efficacy of
      treatment through increasing radiosensitivity, while resistance to radiation
      after administration of cetuximab limits its efficiency. Radiation and drugs can 
      damage the endoplasmic reticulum (ER) homeostatic state and result in ER stress
      (ERS), subsequently causing resistance to radiation and drugs. Whether the ERS
      pathway is involved in radioresistance after administration of cetuximab has not 
      been reported. Herein, we show that cetuximab could increase the radiosensitivity
      of FaDu cells but not Detroit562 cells. In addition, cetuximab inhibited the
      radiation-induced activation of the ERS signalling pathway IRE1alpha/ATF6-GRP78
      in FaDu cells, while this effect was absent in Detroit562 cells. Silencing GRP78 
      increased the radiosensitivity of oropharyngeal carcinoma cells and inhibited
      radiation-induced DNA double-strand-break (DSB) repair and autophagy. More
      interestingly, silencing GRP78 abrogated resistance to cetuximab and radiation in
      Detroit562 cells and had a synergistic effect with cetuximab in increasing the
      radiosensitivity of FaDu cells. Immunohistochemistry showed that overexpression
      of both GRP78 and EGFR was associated with a poor prognosis in oropharyngeal
      carcinoma patients (P&lt;0.05). Overall, the results of this study show that
      radioresistance after EGFR inhibition by cetuximab is mediated by the ERS
      signalling pathway IRE1alpha/ATF6-GRP78. This suppression was consequently unable
      to inhibit radiation-induced DSB repair and autophagy in oropharyngeal carcinoma 
      cells, which conferred resistance to radiotherapy and cetuximab. These results
      suggest that the cooperative effects of radiotherapy and cetuximab could be
      further improved by inhibiting GRP78 in non-responsive oropharyngeal carcinoma
      patients.
FAU - Sun, Chaonan
AU  - Sun C
AD  - Department of Radiotherapy, the First Hospital of China Medical University,
      Shenyang, Liaoning, China.
FAU - Han, Chuyang
AU  - Han C
AD  - Department of Radiotherapy, the First Hospital of China Medical University,
      Shenyang, Liaoning, China.
FAU - Jiang, Yuanjun
AU  - Jiang Y
AD  - Department of Urology, the First Hospital of China Medical University, Shenyang, 
      Liaoning, China.
FAU - Han, Ning
AU  - Han N
AD  - Department of Radiotherapy, the First Hospital of China Medical University,
      Shenyang, Liaoning, China.
FAU - Zhang, Miao
AU  - Zhang M
AD  - Department of Radiotherapy, the First Hospital of China Medical University,
      Shenyang, Liaoning, China.
FAU - Li, Guang
AU  - Li G
AD  - Department of Radiotherapy, the First Hospital of China Medical University,
      Shenyang, Liaoning, China.
FAU - Qiao, Qiao
AU  - Qiao Q
AUID- ORCID: http://orcid.org/0000-0002-6841-3771
AD  - Department of Radiotherapy, the First Hospital of China Medical University,
      Shenyang, Liaoning, China.
LA  - eng
PT  - Journal Article
DEP - 20171212
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (ATF6 protein, human)
RN  - 0 (Activating Transcription Factor 6)
RN  - 0 (Heat-Shock Proteins)
RN  - 0 (molecular chaperone GRP78)
RN  - EC 2.7.10.1 (Receptor, Epidermal Growth Factor)
RN  - EC 2.7.11.1 (ERN1 protein, human)
RN  - EC 2.7.11.1 (Protein-Serine-Threonine Kinases)
RN  - EC 3.1.- (Endoribonucleases)
RN  - PQX0D8J21J (Cetuximab)
SB  - IM
MH  - Activating Transcription Factor 6/metabolism
MH  - Apoptosis
MH  - Autophagy
MH  - Carcinoma, Squamous Cell/metabolism/*pathology
MH  - Cell Line, Tumor
MH  - Cetuximab/*pharmacology
MH  - DNA Damage
MH  - DNA Repair
MH  - Endoplasmic Reticulum Stress
MH  - Endoribonucleases/metabolism
MH  - Heat-Shock Proteins/*antagonists &amp; inhibitors
MH  - Humans
MH  - Oropharyngeal Neoplasms/metabolism/*pathology
MH  - Protein-Serine-Threonine Kinases/metabolism
MH  - Radiation Tolerance/*drug effects
MH  - Receptor, Epidermal Growth Factor/*antagonists &amp; inhibitors
MH  - Signal Transduction
PMC - PMC5726659
EDAT- 2017/12/13 06:00
MHDA- 2018/01/05 06:00
CRDT- 2017/12/13 06:00
PHST- 2017/06/13 00:00 [received]
PHST- 2017/11/15 00:00 [accepted]
PHST- 2017/12/13 06:00 [entrez]
PHST- 2017/12/13 06:00 [pubmed]
PHST- 2018/01/05 06:00 [medline]
AID - 10.1371/journal.pone.0188932 [doi]
AID - PONE-D-17-22513 [pii]
PST - epublish
SO  - PLoS One. 2017 Dec 12;12(12):e0188932. doi: 10.1371/journal.pone.0188932.
      eCollection 2017.