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

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.

Comprehensive analysis of cancer hallmarks in cutaneous melanoma and identification of a novel unfolded protein response as a prognostic signature

“…Afterwards, combined with clinical survival information, we found unfolded protein response was the most significant pathway correlated with OS of melanoma patients. Obviously, the unfolded protein response has been recognized as a crucial role in tumor progression and metastasis [ 29 , 30 ]. Numerous researches showed that unfolded protein response related genes (UPRRGs) are highly expressed in many cancers including colorectal, prostate, lung cancers, ovarian and breast [ 31 – 35 ].…”

BRAF inhibition causes resilience of melanoma cell lines by inducing the secretion of FGF1

“…It was previously described that BRAF inhibition is able to induce the unfolded protein response (UPR) in melanoma cells 37 . Interestingly, another study recently demonstrated that the UPR can trigger the expression of FGF1 and FGF2 in melanoma cells 38 , thus raising the possibility that the BRAF inhibition causes UPR next to senescence and thereby leads to the secretion of protective FGF1. Potential differences in UPR between different cell lines could explain why some cells are potent FGF1 inducers after BRAF/MEK inhibitor treatment (e.g., A375 cells), why others are not (e.g., M14 cells).…”

Emerging Roles of the Endoplasmic Reticulum Associated Unfolded Protein Response in Cancer Cell Migration and Invasion

“…PERK activation also increases VEGFA expression in medulloblastoma, which favors tumor migration through an autocrine manner by interacting with its receptor VEGFR2 [160]. In melanoma, both ATF6 and PERK branches of the UPR are involved in the induction of the fibroblast growth factors FGF1/2 increasing cancer cell migration in vitro [161].…”