The calcium-binding protein S100B reduces IL6 production in malignant melanoma via inhibition of RSK cellular signaling

S100B is frequently elevated in malignant melanoma. A regulatory mechanism was uncovered here in which elevated S100B lowers mRNA and secreted protein levels of interleukin-6 (IL6) and inhibits an autocrine loop whereby IL6 activates STAT3 signaling. Our results showed that S100B affects IL6 express...

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Bibliographic Details
Published in:PloS one 2021-08, Vol.16 (8), p.e0256238
Main Authors: Alasady, Milad J, Terry, Alexander R, Pierce, Adam D, Cavalier, Michael C, Blaha, Catherine S, Adipietro, Kaylin A, Wilder, Paul T, Weber, David J, Hay, Nissim
Format: Article
Language:English
Subjects:
Autocrine signalling
Biochemistry
Biology and Life Sciences
Calcium
Calcium-binding protein
Calcium-binding proteins
Calcium-Binding Proteins - genetics
Cell Line, Tumor
Cell lines
Cellular signal transduction
Cold
Cyclic AMP response element-binding protein
Cyclic AMP Response Element-Binding Protein - genetics
Cytoplasm
Cytoplasm - genetics
Data analysis
Development and progression
Diagnosis
Doxycycline - pharmacology
Funding
Gene Expression Regulation, Neoplastic - drug effects
Health aspects
Humans
Interleukin 6
Interleukin-6 - genetics
Kinases
Medicine
Medicine and Health Sciences
Melanoma
Melanoma - drug therapy
Melanoma - genetics
Melanoma - pathology
Molecular biology
Phosphorylation
Physiological aspects
Proteins
Regulatory mechanisms (biology)
Research and Analysis Methods
Ribosomal protein S6 kinase
Ribosomal Protein S6 Kinases, 90-kDa - genetics
Ribosomal proteins
Risk factors
S100 Calcium Binding Protein beta Subunit - genetics
S100b protein
Signal transduction
Signal Transduction - drug effects
Signaling
Skin cancer
Stat3 protein
STAT3 Transcription Factor - genetics
Substrates
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Summary:S100B is frequently elevated in malignant melanoma. A regulatory mechanism was uncovered here in which elevated S100B lowers mRNA and secreted protein levels of interleukin-6 (IL6) and inhibits an autocrine loop whereby IL6 activates STAT3 signaling. Our results showed that S100B affects IL6 expression transcriptionally. S100B was shown to form a calcium-dependent protein complex with the p90 ribosomal S6 kinase (RSK), which in turn sequesters RSK into the cytoplasm. Consistently, S100B inhibition was found to restore phosphorylation of a nuclear located RSK substrate, CREB, which is a potent transcription factor for IL6 expression. Thus, elevated S100B reduces IL6-STAT3 signaling via RSK signaling pathway in malignant melanoma. Indeed, the elevated S100B levels in malignant melanoma cell lines correspond to low levels of IL6 and p-STAT3.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0256238