Abstract
Metastatic melanoma is the most aggressive type of skin cancer. Previously, we identified the plasma membrane Ca2+ pump isoform 4b (PMCA4b or ATP2B4) as a putative metastasis suppressor in BRAF mutant melanoma cells. Metastasis suppressors are often downregulated in cancer, therefore, it is important to identify the pathways involved in their degradation. Here, we studied the role of p38 MAPK in PMCA4b degradation and its effect on melanoma metastasis. We found that activation of p38 MAPK induces internalization and subsequent degradation of PMCA4b through the endo/lysosomal system that contributes to the low PMCA4b steady-state protein level of BRAF mutant melanoma cells. Moreover, BRAF wild type cell models including a doxycycline-inducible HEK cell system revealed that p38 MAPK is a universal modulator of PMCA4b endocytosis. Inhibition of the p38 MAPK pathway markedly reduced migration, colony formation and metastatic activity of BRAF mutant cells in vitro partially through an increase in PMCA4b and a decrease in β4 integrin abundance. In conclusion, our data suggest that the p38 MAPK pathway plays a key role in PMCA4b degradation and inhibition of this pathway—by increasing the stability of PMCA4b—may provide a potential therapeutic target for inhibition of melanoma progression and metastasis.
Highlights
Melanoma is an aggressive type of skin cancer that develops from the pigment melanin producing melanocytes
We found that PMCA4b expression was downregulated in BRAF mutant melanoma cell lines and inhibition of the Ras-BRAF-MEK-ERK pathway markedly increased it at both the mRNA and protein levels [17]
We found that inhibition of the p38 MAPK pathway strongly enhanced PMCA4b protein level and this effect was specific to the BRAF mutant cells
Summary
Melanoma is an aggressive type of skin cancer that develops from the pigment melanin producing melanocytes. Resulting in DNA damage and accumulation of genetic mutations that eventually lead to cancer [1]. A mutation in the kinase BRAF is observed in approximately 50% of melanomas. Most of these mutations are at codon 600, and over 90% of them are point mutations resulting in a glutamic acid to valine substitution (BRAFV600E ) [2]. This mutation causes constitutive activation of the BRAF/MEK/ERK. Other signalling pathways could be affected by BRAF mutation. An interplay between members of the MAPK pathways—ERK, p38 MAPK and c-Jun N-terminal kinase (JNK)—and NFκB in melanoma progression and therapy resistance has been reported [4,5,6]
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.
