Journal Article

P38 MAPK Promotes Migration and Metastatic Activity of BRAF Mutant Melanoma Cells by Inducing Degradation of PMCA4b

Kállay, Enikő, Cserepes, Mihály, Tóth, Sarolta, Enyedi, Ágnes, Naffa, Randa, Hegedűs, Luca, Grusch, Michael, Reményi, Attila, Kelemen, Kornélia, Tóvári, József, Pászty, Katalin, Singh, Neha, Vogel, Lisa

2020

Overview

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.

• Publisher: MDPI AG,MDPI
• Subject: Antibodies / BRAF mutant melanoma / Ca2+-transporting ATPase / Calcium / Calcium - metabolism / calcium signaling / Cancer therapies / Cell adhesion & migration / Cell culture / Cell cycle / Cell Cycle Checkpoints - drug effects / Cell Death - drug effects / Cell Line, Tumor / Cell Membrane - drug effects / Cell Membrane - metabolism / Cell Movement - genetics / Cell Proliferation - drug effects / Degradation / Doxycycline / Endocytosis / Endocytosis - drug effects / Endosomes - drug effects / Endosomes - metabolism / Homeostasis / Humans / Internalization / JNK Mitogen-Activated Protein Kinases - metabolism / Kinases / Laboratories / Lysosomes - drug effects / Lysosomes - metabolism / MAP kinase / Melanoma / Melanoma - enzymology / Melanoma - genetics / Melanoma - pathology / Melanoma - ultrastructure / Metastases / Metastasis / Mutants / Mutation / Mutation - genetics / Neoplasm Metastasis / NF-kappa B - metabolism / p38 mitogen-activated protein kinase (MAPK) / p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors / p38 Mitogen-Activated Protein Kinases - metabolism / plasma membrane Ca2+ATPase isoform 4b / Plasma Membrane Calcium-Transporting ATPases - metabolism / Protein Kinase Inhibitors - pharmacology / Protein Stability - drug effects / Protein Transport - drug effects / Proteins / Proteolysis / Proto-Oncogene Proteins B-raf - genetics / Skin cancer / Skin Neoplasms - enzymology / Skin Neoplasms - genetics / Skin Neoplasms - pathology / Skin Neoplasms - ultrastructure / Spheroids, Cellular - drug effects / Spheroids, Cellular - metabolism / Spheroids, Cellular - pathology / Therapeutic applications / Tumor Stem Cell Assay / Up-Regulation - drug effects / Up-Regulation - genetics