The unfolded protein response impacts melanoma progression by enhancing FGF expression and can be antagonized by a chemical chaperone

Karin Eigner, Yüksel Filik, Florian Mark, Birgit Schütz, Günter Klambauer, Richard Moriggl, Markus Hengstschläger, Herbert Stangl, Mario Mikula, Clemens Röhrl

Research output: Contribution to journalArticlepeer-review

13 Citations (Scopus)

Abstract

The mechanisms hallmarking melanoma progression are insufficiently understood. Here we studied the impact of the unfolded protein response (UPR) - a signalling cascade playing ambiguous roles in carcinogenesis - in melanoma malignancy. We identified isogenic patient-derived melanoma cell lines harboring BRAFV600E-mutations as a model system to study the role of intrinsic UPR in melanoma progression. We show that the activity of the three effector pathways of the UPR (ATF6, PERK and IRE1) was increased in metastatic compared to non-metastatic cells. Increased UPR-activity was associated with increased flexibility to cope with ER stress. The activity of the ATF6- and the PERK-, but not the IRE-pathway, correlated with poor survival in melanoma patients. Using whole-genome expression analysis, we show that the UPR is an inducer of FGF1 and FGF2 expression and cell migration. Antagonization of the UPR using the chemical chaperone 4-phenylbutyric acid (4-PBA) reduced FGF expression and inhibited cell migration and viability. Consistently, FGF expression positively correlated with the activity of ATF6 and PERK in human melanomas. We conclude that chronic UPR stimulates the FGF/FGF-receptor signalling axis and promotes melanoma progression. Hence, the development of potent chemical chaperones to antagonize the UPR might be a therapeutic approach to target melanoma.

Original languageEnglish
Article number17498
Pages (from-to)17498
JournalScientific Reports
Volume7
Issue number1
DOIs
Publication statusPublished - 13 Dec 2017
Externally publishedYes

Keywords

  • Animals
  • Antineoplastic Agents/pharmacology
  • Biomarkers, Tumor/metabolism
  • Butylamines/pharmacology
  • Cell Line, Tumor
  • Cell Movement/physiology
  • Cell Survival/drug effects
  • Disease Progression
  • Endoplasmic Reticulum Stress/physiology
  • Fibroblast Growth Factors/metabolism
  • Gene Expression Regulation, Neoplastic/drug effects
  • Humans
  • Melanocytes/drug effects
  • Melanoma/drug therapy
  • Mice
  • Mutation
  • Neoplasm Transplantation
  • Proto-Oncogene Proteins B-raf/genetics
  • Unfolded Protein Response/drug effects

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