Abstract
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.
Highlights
In vertebrates, normal S100B expression is cell-specific and found in chondrocytes, myoblasts, skeletal myofibrils, astrocytes, and melanocytes, but it is often highly overexpressed in cancers including most notably gliomas and malignant melanoma [1,2,3]
While several prognostic melanocytic biomarkers are available for melanoma such as the melanoma inhibitory activity (MIA) protein, lactate dehydrogenase (LDH), HMB 45, and Melan A/Mart 1, the S100B protein is regarded as being most useful since elevated serum levels of S100B correlate highly with poor patient response to therapies, increased cancer recurrence, and lower survival rates [4,5,6,7]
An increase in the mRNA expression (Fig 1A; > 10-fold) and secreted protein levels (> 50-fold; Fig 1B) of IL6 were identified when S100B expression was silenced (Fig 1C, and S1A Fig). To further confirm these results and to mitigate any off- target effect from shRNA, transient silencing of S100B in WM115 cells via two unique functionally validated siRNA sequences showed an increase of the mRNA expression of IL6 (S1B and S1C Fig)
Summary
Normal S100B expression is cell-specific and found in chondrocytes, myoblasts, skeletal myofibrils, astrocytes, and melanocytes, but it is often highly overexpressed in cancers including most notably gliomas and malignant melanoma [1,2,3]. While several prognostic melanocytic biomarkers are available for melanoma such as the melanoma inhibitory activity (MIA) protein, lactate dehydrogenase (LDH), HMB 45, and Melan A/Mart 1, the S100B protein is regarded as being most useful since elevated serum levels of S100B correlate highly with poor patient response to therapies, increased cancer recurrence, and lower survival rates [4,5,6,7].
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