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Hypoxic regulation of the PERK/ATF4/LAMP3‐arm of the unfolded protein response in head and neck squamous cell carcinoma
Author(s) -
Nagelkerke Anika,
Sweep Fred C. G. J.,
Stegeman Hanneke,
Grénman Reidar,
Kaanders Johannes H. A. M.,
Bussink Johan,
Span Paul N.
Publication year - 2015
Publication title -
head and neck
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.012
H-Index - 127
eISSN - 1097-0347
pISSN - 1043-3074
DOI - 10.1002/hed.23693
Subject(s) - atf4 , unfolded protein response , head and neck squamous cell carcinoma , cancer research , protein kinase r , endoplasmic reticulum , medicine , biology , cell cycle , microbiology and biotechnology , cancer , head and neck cancer , cyclin dependent kinase 2
Background The purpose of this study was to examine the hypoxic regulation of the PKR‐like endoplasmic reticulum kinase (PERK)/activating transcription factor‐4 (ATF4)/lysosome‐associated membrane protein 3 (LAMP3)‐arm of the unfolded protein response (UPR) in head and neck squamous cell carcinoma (HNSCC). Methods LAMP3 expression was determined in patient biopsies by immunohistochemistry and correlated to clinicopathological parameters. mRNA and protein expression for PERK, ATF4, and LAMP3 was evaluated after hypoxic exposure of HNSCC cell lines. Results In patients with HNSCC, high LAMP3 expression correlated with N classification ( p = .019) and the occurrence of distant metastases during follow‐up ( p = .039). Patients with high LAMP3 levels had a worse metastasis‐free survival ( p = .008). Intriguingly, LAMP3 expression was localized exclusively in normoxic areas of tumors and xenografts. Expression of PERK, p‐PERK, p‐eIF2α, ATF4, and LAMP3 was not universally induced in hypoxic HNSCC cell lines. Exposure to endoplasmic reticulum‐stress stimulated PERK, ATF4, and LAMP3 expression. Conclusion LAMP3 is relevant for prognosis in HNSCC. However, the PERK/ATF4/LAMP3‐arm of the UPR responds differently to hypoxia in HNSCC compared to other tumor types. © 2014 Wiley Periodicals, Inc. Head Neck 37: 896–905, 2015