Inverse regulation of melanoma growth and migration by Orai1/STIM2-dependent calcium entry.
Spontaneous melanoma phenotype switching is controlled by unknown environmental factors and may determine melanoma outcome and responsiveness to anticancer therapy. We show that Orai1 and STIM2 are highly expressed and control store-operated Ca(2+) entry in human melanoma. Lower extracellular Ca(2+) or silencing of Orai1/STIM2 caused a decrease in intracellular Ca(2+) , which correlated with enhanced proliferation and increased expression of microphthalmia-associated transcription factor, a marker for proliferative melanoma phenotype. In contrast, the invasive and migratory potential of melanoma cells was reduced upon silencing of Orai1 and/or STIM2. Accordingly, markers for a non-proliferative, tumor-maintaining phenotype such as JARID1B and Brn2 decreased. Immunohistochemical staining of primary melanomas and lymph node metastases revealed a heterogeneous distribution of Orai1 and STIM2 with elevated expression in the invasive rim of the tumor. In summary, our results support a dynamic model in which Orai1 and STIM2 inversely control melanoma growth and invasion. Pharmacological tuning of Orai1 and particularly STIM2 might thus prevent metastatic spread and render melanomas more susceptible to conventional therapy.
Department of Dermatology, Venereology and Allergology, University Hospital of the Saarland, Homburg, Germany.
Hedwig
H
Stanisz
Stephanie
S
Saul
Cornelia S L
CS
Müller
Reinhard
R
Kappl
Barbara A
BA
Niemeyer
Thomas
T
Vogt
Markus
M
Hoth
Alexander
A
Roesch
Ivan
I
Bogeski
D000818:Animals; D001932:Brain Neoplasms / Q000556:secondary; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000235:genetics / Q000502:physiology*; D020013:Calcium Signaling / Q000502:physiology*; D002417:Cattle; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D002455:Cell Division; D045744:Cell Line, Tumor; D002465:Cell Movement; D003470:Culture Media / Q000494:pharmacology; D045604:Extracellular Fluid / Q000378:metabolism; D006031:Glycosylation; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D017136:Ion Transport / Q000187:drug effects; D056484:Jumonji Domain-Containing Histone Demethylases / Q000096:biosynthesis / Q000235:genetics; D008207:Lymphatic Metastasis; D008543:Melanins / Q000096:biosynthesis; D008545:Melanoma / Q000378:metabolism / Q000473:pathology* / Q000556:secondary; D009361:Neoplasm Invasiveness / Q000503:physiopathology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics; D000071740:ORAI1 Protein; D050809:POU Domain Factors / Q000096:biosynthesis / Q000235:genetics; D011499:Protein Processing, Post-Translational; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics; D044967:Serum; D000071738:Stromal Interaction Molecule 2
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D015815:Cell Adhesion Molecules; D003470:Culture Media; D018398:Homeodomain Proteins; D008543:Melanins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000071740:ORAI1 Protein; C510746:ORAI1 protein, human; D050809:POU Domain Factors; D034741:RNA, Small Interfering; D012097:Repressor Proteins; C513279:STIM2 protein, human; D000071738:Stromal Interaction Molecule 2; C085076:transcription factor Brn-2; D056484:Jumonji Domain-Containing Histone Demethylases; C119611:KDM5B protein, human
Orai1; STIM2; calcium; invasion; melanoma; migration; proliferation