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

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). 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. 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. 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.