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

PLoS One. 2021 Aug 19;16(8):e0256238. doi: 10.1371/journal.pone.0256238. eCollection 2021.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Calcium-Binding Proteins / genetics
  • Cell Line, Tumor
  • Cyclic AMP Response Element-Binding Protein / genetics
  • Cytoplasm / genetics
  • Doxycycline / pharmacology
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Interleukin-6 / genetics*
  • Melanoma / drug therapy
  • Melanoma / genetics*
  • Melanoma / pathology
  • Ribosomal Protein S6 Kinases, 90-kDa / genetics*
  • S100 Calcium Binding Protein beta Subunit / genetics*
  • STAT3 Transcription Factor / genetics*
  • Signal Transduction / drug effects


  • CREB1 protein, human
  • Calcium-Binding Proteins
  • Cyclic AMP Response Element-Binding Protein
  • Interleukin-6
  • S100 Calcium Binding Protein beta Subunit
  • S100B protein, human
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Ribosomal Protein S6 Kinases, 90-kDa
  • Doxycycline