Friend or Foe: S100 Proteins in Cancer

Abstract

S100 proteins are widely expressed small molecular EF-hand calcium-binding proteins of vertebrates, which are involved in numerous cellular processes, such as Ca²⁺ homeostasis, proliferation, apoptosis, differentiation, and inflammation. Although the complex network of S100 signalling is by far not fully deciphered, several S100 family members could be linked to a variety of diseases, such as inflammatory disorders, neurological diseases, and also cancer. The research of the past decades revealed that S100 proteins play a crucial role in the development and progression of many cancer types, such as breast cancer, lung cancer, and melanoma. Hence, S100 family members have also been shown to be promising diagnostic markers and possible novel targets for therapy. However, the current knowledge of S100 proteins is limited and more attention to this unique group of proteins is needed. Therefore, this review article summarises S100 proteins and their relation in different cancer types, while also providing an overview of novel therapeutic strategies for targeting S100 proteins for cancer treatment.

Keywords: Ca2+-dependent signalling; S100 proteins; biomarkers; cancer therapy.

Figure 1

S100 signalling in breast cancer. Intracellular S100A4 interacts with cytoskeletal proteins, such as actin, non-muscle myosin heavy chain IIA (NMIIA), and tropomyosin, which promotes cell motility. Besides, S100A4 can induce epithelial–mesenchymal transition (EMT) by regulating the expression of matrix metallopeptidases 2 (MMP2), leading to invasion and metastasis. Extracellular S100A4, located in the tumour microenvironment (TME), induces the release of pro-inflammatory factors (e.g., IL-6, IL-8, and CXCL10). These cytokines then convert monocytes into tumour-associated macrophages (TAMs), which in return, promote EMT, proliferation, and drug resistance of the tumour cells. The binding of extracellular S100A7 to the receptor for advanced glycation end products (RAGE) induces mitogen-activated protein kinase (MAPK) and nuclear factor “kappa-light-chain-enhancer” of activated B-cells (NF-κB) signalling, resulting in tumour growth and metastasis. Increased NF-κB activity was observed in S100A7-overexpressing breast cancer cells, associated with evaluated levels of matrix metalloproteinase 9 (MMP9) and vascular endothelial growth factor (VEGF), resulting in proliferation and invasion. The binding of S100A7 and RAGE also leads to the recruitment of TAMs, which then promote further tumour growth, angiogenesis, and metastasis by expressing chemokine (C-C motif) ligand 2 (CCL2), cyclooxygenase-2 (COX2), and VEGF. Intracellular S100A7 interacts with the transcriptional cofactor COP9 constitutive photomorphogenic homolog subunit 5 (COPS5), which in turn promotes the expression of AP-1 and NF-κB, resulting in enhanced tumour growth and invasion. S100A8/S100A9 enhances breast cancer cell growth by inducing MAPK signalling in a RAGE-dependent manner. In addition, RAGE mediates cell migration by promoting actin polymerisation and EMT, leading to metastasis and invasion.

Figure 2

S100 signalling in lung cancer. Extracellular S100A4 inhibits autophagy and induces Wnt signalling by interacting with the receptor for advanced glycation end products (RAGE) and intracellular S100A4 additionally activates β-catenin, resulting in increased proliferation and enhanced viability of lung cancer cells. S100A4 also induces the expression of (MMP9) by activating nuclear factor “kappa-light-chain-enhancer” of activated B-cells (NF-κB), thereby promoting invasion and metastasis. S100A7 is most likely involved in adenocarcinoma (ADC) to squamous cell carcinoma (SSC) transdifferentiation of lung cancer cells, by upregulating the SSC marker DNp63 and downregulation of the ADC markers thyroid transcription factor 1 (TTF1) and aspartic proteinase napsin (napsin A). In this context, an inverse correlation of S100A7 and yes-associated protein (YAP) was observed. Moreover, S100A7 seems to activate NF-κB-dependent cell proliferation. Within lung cancer-derived brain metastasis cells, S100B was shown to upregulate the expression of B-cell lymphoma 2 (Bcl-2) and B-cell lymphoma extra-large (Bcl-xL), indicating that S100B is capable of suppressing apoptosis.

Figure 3

S100 signalling in melanoma. Extracellular S100A4 binds to the receptor for advanced glycation end products (RAGE) and thereby activates nuclear factor “kappa-light-chain-enhancer” of activated B-cells (NF-κB), resulting in the release of cytokines such as tumour necrosis factor α (TNFα). These cytokines then promote angiogenesis and recruitment of monocytes, creating an inflammatory milieu in the tumour environment. Furthermore, extracellular S100A4 also decreases the expression of occluding and vascular endothelial cadherin (VE)-cadherin in endothelial cells (ECs), thereby disrupting cell–cell adhesion and enabling the tumour cells to transmigrate through the EC monolayer into the bloodstream. The release of S100A8/S100A9 can be induced by UV radiation-exposed keratinocytes, and extracellular S100A8/S100A9 then promotes proliferation and migration of melanocytes via RAGE signalling. The interaction between S100A8/S100A9 and RAGE can lead to increased levels of the metalloproteinases MMP2, MMP9, and MMP14 in melanoma cells, thereby enhancing metastatic properties. In addition to RAGE, S100A8/A9 also binds to the melanoma cell adhesion molecule (MCAM), thereby activating tumour progression locus 2 (TPL2) and stimulating the transcription factor ETS translocation variant 4 (ETV4), leading to the induction of MMP25 and promoting melanoma lung metastasis. The homodimer of S100A9 additionally interacts with extracellular matrix metalloprotease inducer (EMMPRIN), which activates TNF receptor-associated factor (TRAF2)-dependent NF-κB signalling and the upregulation of cytokines such as TNFα, chemokine (C-X-C motif) ligand 1 (CXCL1), CXCL2, and CXCL3, resulting in metastasis. S100B inhibits the phosphorylation of ribosomal S6 kinase (RSK) by extracellular signal-regulated kinase (ERK) in a Ca²⁺-dependent manner so that RSK remains in the cytoplasm, leading to improved tumour survival. S100B also inhibits p53 activity at the protein level, thereby preventing p53-dependent apoptosis.