Open AccessThe calcium-binding protein S100B reduces IL6 production in malignant melanoma via inhibition of RSK cellular signaling
Author(s) -
Milad J. Alasady,
Alexander R. Terry,
Adam D. Pierce,
Michael C. Cavalier,
Catherine Blaha,
Kaylin A. Adipietro,
Paul T. Wilder,
David J. Weber,
Nissim Hay
Publication year - 2021
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0256238
Subject(s) - autocrine signalling , melanoma , stat3 , signal transduction , ribosomal s6 kinase , phosphorylation , creb , cancer research , transcription factor , biology , microbiology and biotechnology , cell culture , chemistry , biochemistry , p70 s6 kinase 1 , pi3k/akt/mtor pathway , gene , genetics
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.