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.
Highlights
Melanoma is the most aggressive type of skin cancer and its incidence is rising worldwide
We studied isogenic melanoma cell lines harboring BRAFV600E mutations derived from human patients as a model system to analyze intrinsic activation of the unfolded protein response (UPR)
Patient-derived melanoma cells to study the role of the UPR in melanoma progression
Summary
Melanoma is the most aggressive type of skin cancer and its incidence is rising worldwide. HA15, a compound that targets GRP78, induces ER stress leading to cancer cell death in-vitro and in-vivo, even in BRAF inhibitor resistant melanoma cells[13] In these studies, together with numerous studies using chemical inducers of the UPR like thapsigargin or tunicamycin[14,15], the UPR is activated to levels that exceed the intrinsic conditions in tumours. We studied isogenic melanoma cell lines harboring BRAFV600E mutations derived from human patients as a model system to analyze intrinsic activation of the UPR This model system allowed us to study the consequences of intrinsic UPR activity without artificially inducing ER stress and to identify FGF1 and FGF2 as novel UPR targets in melanoma contributing to its progression. We show that melanoma ER stress can be antagonized by the chemical chaperone 4-phenylbutyric acid (4-PBA)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
