Hypoxic regulation of the PERK/ATF4/LAMP3-arm of the unfolded protein response in head and neck squamous cell carcinoma

Anika Nagelkerke; Fred C G J Sweep; Hanneke Stegeman; Reidar Grénman; Johannes H A M Kaanders; Johan Bussink; Paul N Span

doi:10.1002/hed.23693

Hypoxic regulation of the PERK/ATF4/LAMP3-arm of the unfolded protein response in head and neck squamous cell carcinoma

Anika Nagelkerke, Fred C G J Sweep, Hanneke Stegeman, Reidar Grénman, Johannes H A M Kaanders, Johan Bussink, Paul N Span^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

27 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	896-905
Number of pages	10
Journal	Head and Neck: Journal of the Sciences and Specialties of the Head and Neck
Volume	37
Issue number	6
DOIs	https://doi.org/10.1002/hed.23693
Publication status	Published - Jun-2015
Externally published	Yes

Keywords

Activating Transcription Factor 4/genetics
Adult
Aged
Aged, 80 and over
Animals
Blotting, Western
Carcinoma, Squamous Cell/genetics
Cell Hypoxia
Cell Line, Tumor
Cell Survival/genetics
Cohort Studies
Female
Gene Expression Regulation, Neoplastic
Head and Neck Neoplasms/genetics
Heterografts
Humans
Immunohistochemistry
Lysosome-Associated Membrane Glycoproteins/genetics
Male
Middle Aged
Neoplasm Proteins/genetics
Polymerase Chain Reaction/methods
Prognosis
Squamous Cell Carcinoma of Head and Neck
Survival Rate
eIF-2 Kinase/genetics

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Hypoxic regulation of the PERK/ATF4/LAMP3‐arm of the unfolded protein response in head and neck squamous cell carcinoma
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@article{a8ccada5f7a24b5383688b1ce124f648,

title = "Hypoxic regulation of the PERK/ATF4/LAMP3-arm of the unfolded protein response in head and neck squamous cell carcinoma",

abstract = "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.",

keywords = "Activating Transcription Factor 4/genetics, Adult, Aged, Aged, 80 and over, Animals, Blotting, Western, Carcinoma, Squamous Cell/genetics, Cell Hypoxia, Cell Line, Tumor, Cell Survival/genetics, Cohort Studies, Female, Gene Expression Regulation, Neoplastic, Head and Neck Neoplasms/genetics, Heterografts, Humans, Immunohistochemistry, Lysosome-Associated Membrane Glycoproteins/genetics, Male, Middle Aged, Neoplasm Proteins/genetics, Polymerase Chain Reaction/methods, Prognosis, Squamous Cell Carcinoma of Head and Neck, Survival Rate, eIF-2 Kinase/genetics",

author = "Anika Nagelkerke and Sweep, {Fred C G J} and Hanneke Stegeman and Reidar Gr{\'e}nman and Kaanders, {Johannes H A M} and Johan Bussink and Span, {Paul N}",

note = "{\textcopyright} 2014 Wiley Periodicals, Inc.",

year = "2015",

month = jun,

doi = "10.1002/hed.23693",

language = "English",

volume = "37",

pages = "896--905",

journal = "Head and Neck: Journal of the Sciences and Specialties of the Head and Neck",

issn = "1043-3074",

publisher = "Wiley",

number = "6",

}

Hypoxic regulation of the PERK/ATF4/LAMP3-arm of the unfolded protein response in head and neck squamous cell carcinoma. / Nagelkerke, Anika; Sweep, Fred C G J; Stegeman, Hanneke et al.
In: Head and Neck: Journal of the Sciences and Specialties of the Head and Neck, Vol. 37, No. 6, 06.2015, p. 896-905.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Hypoxic regulation of the PERK/ATF4/LAMP3-arm of the unfolded protein response in head and neck squamous cell carcinoma

AU - Nagelkerke, Anika

AU - Sweep, Fred C G J

AU - Stegeman, Hanneke

AU - Grénman, Reidar

AU - Kaanders, Johannes H A M

AU - Bussink, Johan

AU - Span, Paul N

PY - 2015/6

Y1 - 2015/6

N2 - 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.

AB - 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.

KW - Activating Transcription Factor 4/genetics

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Animals

KW - Blotting, Western

KW - Carcinoma, Squamous Cell/genetics

KW - Cell Hypoxia

KW - Cell Line, Tumor

KW - Cell Survival/genetics

KW - Cohort Studies

KW - Female

KW - Gene Expression Regulation, Neoplastic

KW - Head and Neck Neoplasms/genetics

KW - Heterografts

KW - Humans

KW - Immunohistochemistry

KW - Lysosome-Associated Membrane Glycoproteins/genetics

KW - Male

KW - Middle Aged

KW - Neoplasm Proteins/genetics

KW - Polymerase Chain Reaction/methods

KW - Prognosis

KW - Squamous Cell Carcinoma of Head and Neck

KW - Survival Rate

KW - eIF-2 Kinase/genetics

U2 - 10.1002/hed.23693

DO - 10.1002/hed.23693

M3 - Article

C2 - 24634103

SN - 1043-3074

VL - 37

SP - 896

EP - 905

JO - Head and Neck: Journal of the Sciences and Specialties of the Head and Neck

JF - Head and Neck: Journal of the Sciences and Specialties of the Head and Neck

IS - 6

ER -

Hypoxic regulation of the PERK/ATF4/LAMP3-arm of the unfolded protein response in head and neck squamous cell carcinoma

Abstract

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