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

• 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
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0256238

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.