Hypoxic activation of the PERK/eIF2α arm of the unfolded protein response promotes metastasis through induction of LAMP3

Hilda Mujcic, Anika Nagelkerke, Kasper M A Rouschop, Stephen Chung, Naz Chaudary, Paul N Span, Blaise Clarke, Michael Milosevic, Jenna Sykes, Richard P Hill, Marianne Koritzinsky, Bradly G Wouters*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

77 Citations (Scopus)

Abstract

PURPOSE: Conditions of poor oxygenation (hypoxia) are present in many human tumors, including cervix cancer, and are associated with increased risk of metastasis and poor prognosis. Hypoxia is a potent activator of the PERK/eIF2α signaling pathway, a component of the unfolded protein response (UPR) and an important mediator of hypoxia tolerance and tumor growth. Here, the importance of this pathway in the metastasis of human cervix carcinoma was investigated.

EXPERIMENTAL DESIGN: Amplification and expression of LAMP3, a UPR metastasis-associated gene, was examined using FISH and immunofluorescence in a cohort of human cervix tumors from patients who had received oxygen needle electrode tumor oxygenation measurements. To evaluate the importance of this pathway in metastasis in vivo, we constructed a series of inducible cell lines to interfere with PERK signaling during hypoxia and used these in an orthotopic cervix cancer model of hypoxia-driven metastasis.

RESULTS: We show that LAMP3 expression in human cervix tumors is augmented both by gene copy number alterations and by hypoxia. Induced disruption of PERK signaling in established orthotopic xenografts resulted in complete inhibition of hypoxia-induced metastasis to the lymph nodes. This is due, in part, to a direct influence of the UPR pathway on hypoxia tolerance. However, we also find that LAMP3 is a key mediator of hypoxia-driven nodal metastasis, through its ability to promote metastatic properties including cell migration.

CONCLUSION: These data suggest that the association between hypoxia, metastasis, and poor prognosis is due, in part, to hypoxic activation of the UPR and expression of LAMP3. Clin Cancer Res; 19(22); 6126-37. ©2013 AACR.

Original languageEnglish
Pages (from-to)6126-6137
Number of pages12
JournalClinical Cancer Research
Volume19
Issue number22
DOIs
Publication statusPublished - 15-Nov-2013
Externally publishedYes

Keywords

  • Animals
  • Cell Hypoxia
  • Cell Line, Tumor
  • Cell Movement
  • DNA Copy Number Variations
  • Eukaryotic Initiation Factor-2/metabolism
  • Female
  • Gene Dosage
  • Humans
  • Lymphatic Metastasis/genetics
  • Lysosome-Associated Membrane Glycoproteins/genetics
  • Mice
  • Neoplasm Proteins/genetics
  • Neoplasm Transplantation
  • Protein Phosphatase 1/metabolism
  • Signal Transduction/genetics
  • Transplantation, Heterologous
  • Unfolded Protein Response/physiology
  • Uterine Cervical Neoplasms/genetics
  • eIF-2 Kinase/metabolism

Cite this