The plasma membrane Ca2+pump PMCA4b inhibits the migratory and metastatic activity of BRAF mutant melanoma cells.
Oncogenic mutations of BRAF lead to constitutive ERK activity that supports melanoma cell growth and survival. While Ca2+signaling is a well-known regulator of tumor progression, the crosstalk between Ca2+signaling and the Ras-BRAF-MEK-ERK pathway is much less explored. Here we show that in BRAF mutant melanoma cells the abundance of the plasma membrane Ca2+ATPase isoform 4b (PMCA4b, ATP2B4) is low at baseline but markedly elevated by treatment with the mutant BRAF specific inhibitor vemurafenib. In line with these findings gene expression microarray data also shows decreased PMCA4b expression in cutaneous melanoma when compared to benign nevi. The MEK inhibitor selumetinib-similarly to that of the BRAF-specific inhibitor-also increases PMCA4b levels in both BRAF and NRAS mutant melanoma cells suggesting that the MAPK pathway is involved in the regulation of PMCA4b expression. The increased abundance of PMCA4b in the plasma membrane enhances [Ca2+]iclearance from cells after Ca2+entry. Moreover we show that both vemurafenib treatment and PMCA4b overexpression induce marked inhibition of migration of BRAF mutant melanoma cells. Importantly, reduced migration of PMCA4b expressing BRAF mutant cells is associated with a marked decrease in their metastatic potential in vivo. Taken together, our data reveal an important crosstalk between Ca2+signaling and the MAPK pathway through the regulation of PMCA4b expression and suggest that PMCA4b is a previously unrecognized metastasis suppressor.
Department of Pathophysiology and Allergy Research, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria.
Luca
L
Hegedũs
2nd Department of Pathology, Semmelweis University, Budapest, Hungary.|Department of Biological Physics, Eötvös University, Budapest, Hungary.
Tamás
T
Garay
2nd Department of Pathology, Semmelweis University, Budapest, Hungary.
Eszter
E
Molnár
2nd Department of Pathology, Semmelweis University, Budapest, Hungary.
Karolina
K
Varga
2nd Department of Pathology, Semmelweis University, Budapest, Hungary.
Ágnes
Á
Bilecz
National Koranyi Institute of Pulmonology, Budapest, Hungary.
Szilvia
S
Török
2nd Department of Pathology, Semmelweis University, Budapest, Hungary.
Rita
R
Padányi
Molecular Biophysics Research Group of the Hungarian Academy of Sciences and Department of Biophysics, Semmelweis University, Budapest, Hungary.
Katalin
K
Pászty
Department of Medicine I, Institute of Cancer Research, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria.
Matthias
M
Wolf
Department of Medicine I, Institute of Cancer Research, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria.
Michael
M
Grusch
Department of Pathophysiology and Allergy Research, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria.
Enikõ
E
Kállay
National Koranyi Institute of Pulmonology, Budapest, Hungary.|Department of Surgery, Division of Thoracic Surgery, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria.|Department of Thoracic Surgery, National Institute of Oncology-Semmelweis University, Budapest, Hungary.|Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Vienna, Austria.
Balázs
B
Döme
Department of Medicine I, Institute of Cancer Research, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria.
Walter
W
Berger
Department of Surgery, Division of Thoracic Surgery, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria.|Department of Thoracic Surgery, Ruhrlandklinik, University Clinic Essen, Essen, Germany.|Molecular Oncology Research Group of the Hungarian Academy of Sciences and 2nd Department of Pathology, Semmelweis University, Budapest, Hungary.
Balázs
B
Hegedũs
2nd Department of Pathology, Semmelweis University, Budapest, Hungary.|Molecular Oncology Research Group of the Hungarian Academy of Sciences and 2nd Department of Pathology, Semmelweis University, Budapest, Hungary.
Agnes
0000-0002-7366-9376
A
Enyedi
D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016513:Mice, SCID; D018613:Microscopy, Confocal; D009154:Mutation; D009362:Neoplasm Metastasis; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000235:genetics* / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D013449:Sulfonamides / Q000494:pharmacology; D014183:Transplantation, Heterologous; D000077484:Vemurafenib
D004791:Enzyme Inhibitors; D007211:Indoles; D013449:Sulfonamides; D000077484:Vemurafenib; D048493:Proto-Oncogene Proteins B-raf; C507517:ATP2B4 protein, human; D053499:Plasma Membrane Calcium-Transporting ATPases; D002118:Calcium
BRAF mutant melanoma; PMCA4b; calcium signaling; metastasis; migration