title: Signal Sequence Receptor 2 is required for survival of human melanoma cells as part of an unfolded protein response to endoplasmic reticulum stress.
abstract: Current therapy approaches in melanoma targeting have met with the development of resistance and tumour recurrence with a more aggressive phenotype. In a quest for alternative therapy targets, we had previously identified Signal Sequence Receptor 2 (SSR2) as a gene with high expression in a subgroup of human primary melanomas. Now we show that SSR2 exerts a prosurvival functionality in human melanoma cells and that high expression levels of SSR2 are associated with an unfavourable disease outcome in primary melanoma patients. Consistent with SSR's role in translocation of proteins from the ribosome across the endoplasmic reticulum (ER) membrane, our data supports induction of SSR2 as a part of the ER stress response. This response included SSR2 upregulation upon development of therapy resistance to BRAF inhibitors, as well as the dependency of cell survival of BRAF inhibitor-resistant melanoma cells on SSR2. Complementary gain and loss of function data showed the Unfolded Protein Response (UPR) to ER stress as an inducer of SSR2 via transcriptional regulation through X-Box Binding Protein 1s (XBP1s) and support an ER stress-UPR-Transcription Factor XBP1s-SSR2 response axis in human melanocytic cells. Together with its dispensability for survival in normal human cells, these data propose SSR2 as a potential therapeutic target in (therapy-resistant) human melanoma.
authors.affiliation: Division of Immunology Allergy and Infectious Diseases (DIAID), Department of Dermatology, Medical University of Vienna, Waehringer Guertel 18-20, Vienna A-1090, Austria.
authors.forename: Bhavuk
authors.initials: B
authors.lastname: Garg
authors.affiliation: Division of Immunology Allergy and Infectious Diseases (DIAID), Department of Dermatology, Medical University of Vienna, Waehringer Guertel 18-20, Vienna A-1090, Austria, Present address: Biochemical-Pharmacological Center, University of Marburg, Karl-von-Frisch-Straße, Marburg 35032, Germany.
authors.forename: Gaurav
authors.initials: G
authors.lastname: Pathria
authors.affiliation: Division of Immunology Allergy and Infectious Diseases (DIAID), Department of Dermatology, Medical University of Vienna, Waehringer Guertel 18-20, Vienna A-1090, Austria.
authors.forename: Christine
authors.initials: C
authors.lastname: Wagner
authors.affiliation: Division of Immunology Allergy and Infectious Diseases (DIAID), Department of Dermatology, Medical University of Vienna, Waehringer Guertel 18-20, Vienna A-1090, Austria.
authors.forename: Margarita
authors.initials: M
authors.lastname: Maurer
authors.affiliation: Division of Immunology Allergy and Infectious Diseases (DIAID), Department of Dermatology, Medical University of Vienna, Waehringer Guertel 18-20, Vienna A-1090, Austria, stephan.wagner@meduniwien.ac.at.
authors.forename: Stephan N
authors.initials: SN
authors.lastname: Wagner
mesh_terms: D002135:Calcium-Binding Proteins / Q000235:genetics*; D002460:Cell Line; D002470:Cell Survival; D059865:Endoplasmic Reticulum Stress; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008545:Melanoma / Q000378:metabolism* / Q000503:physiopathology; D008562:Membrane Glycoproteins / Q000235:genetics*; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D018000:Receptors, Peptide / Q000235:genetics*; D015533:Transcriptional Activation; D056811:Unfolded Protein Response
chemical_list: D002135:Calcium-Binding Proteins; D008562:Membrane Glycoproteins; D018160:Receptors, Cytoplasmic and Nuclear; D018000:Receptors, Peptide; C066973:signal sequence receptor