ReviewPost screenInterfering with S100B–effector protein interactions for cancer therapy
Introduction
S100B is a homodimeric Ca2+-binding protein that is involved in the regulation of intracellular and extracellular processes 1, 2. Structurally, S100B contains four helices in each subunit. The canonical 10–12-residue EF-hand comprises helix 3, helix 4, and loop 2, whereas the 14-residue N-terminal pseudo-EF-hand comprises helix 1, helix 2, and loop 1. When S100B binds to Ca2+, helix 3 undergoes a significant conformational change to become perpendicular to helix 4, revealing a hydrophobic pocket for interaction with its targets 3, 4, 5. Unlike other proteins, S100B is not a ubiquitous protein, and its expression is restricted to astrocytes and melanocytes [6]. As an intracellular regulator, S100B mainly localizes in the cytoplasm and regulates cell proliferation, Ca2+ homeostasis, protein phosphorylation, enzyme activity, and metabolism via physical interactions with its target molecules, including the tumor suppressor p53, CapZ, the RAGE receptor, Hdm2, NDR kinase protein kinase Cα, the dopamine D2 receptor, and ribosomal S6 kinase 1 (RSK1) [7]. When S100B is actively released by astrocytes and adipocytes, it acts as an extracellular signal [8].
At low physiological levels, S100B protects neurons against apoptosis and stimulates astrocyte proliferation via upregulating the antiapoptotic factor, Bcl-2, via engagement of RAGE and activation of the MAPK pathway [8], whereas, at high levels, S100B causes neuronal death via the Akt/p21 pathway 6, 8. Moreover, accumulating evidence reveals that S100B is overexpressed in various malignant tumors and that S100B–effector proteins interactions are important for tumor growth. For example, S100B can interact with p53 to inhibit p53 function, whereas disrupting S100B–p53 interference can suppress tumor growth 9, 10. The high binding affinity of the S100B and RAGE interaction was observed in glioma cells, whereas blocking the S100B–RAGE interaction suppressed STAT3 pathway to reduce glioma growth in vivo [10]. In addition, S100B directly binds to RSK as well as retaining RSK in the cytoplasm, and promotes aberrant ERK/RSK activity to induce cancer cell proliferation [11]. Although S100B–effector protein interactions are not fully understood, research demonstrates the modulation of the S100B–effector protein interaction as a promising strategy for S100B-dependent tumor therapy.
Computer-aided approaches, including VS, have been utilized to assist the development of protein–protein interaction (PPI) inhibitors [12]. Although some S100B inhibitors have been reported using VS, most target the S100B–p53 interaction for melanoma therapy [10]. In this review, we provide an overview of S100B–effector protein interaction inhibitor discovery using VS. We discuss promising S100B–effector protein interaction targets, especially those with characterized 3D structures that enable in silico analysis for S100B-dependent cancer therapy drug discovery.
Section snippets
Role of S100B in tumorigenesis
Overexpressed S100B is observed in various highly malignant cancers and can physically interacts with its target effector proteins to regulate tumor growth (Fig. 1) 8, 13, 14. Here, we discuss the role of S100B in the tumorigenesis of various human cancers.
Application of VS for S100B–effector protein interaction inhibitor discovery
Computer-aided drug design (CADD), including VS, has emerged as an efficient approach to identify small-molecule PPI modulators [12]. VS methods can be traditionally divided into two broad types: structure-based VS (SBVS) and ligand-based VS (LBVS). In general, SBVS depends on the knowledge of the target protein 3D structure to screen target molecules, whereas LBVS is based on knowledge of known active and inactive molecules from a ligand database [40]. Integrating SBVS and LBVS approaches can
Targeting S100B–effector protein interactions for cancer therapy
As described earlier, S100B dysfunction induces cancer cell proliferation and metastasis via regulating protein phosphorylation, transcription, enzyme activity, and metabolism 60, 61, 62. Therefore, interfering with S100B–effector protein interactions is an emerging strategy for S100B-dependent cancer therapy 3, 15, 16. However, although a few S100B–p53 interaction inhibitors have been identified via structure-based and ligand-based VS campaigns, reports of the discovery of other S100B–effector
Concluding remarks and perspective
S100B is overexpressed in several highly malignant cancers and exerts its biological function by physical interactions with its target molecules to induce cancer cell proliferation and metastasis. Up to now, one FDA-approved inhibitor (SBi1) has been repurposed for melanoma therapy and is in preclinical trials. Although several S100B inhibitors have been reported, most have targeted the S100B–p53 PPI for melanoma therapy. Hence, there is scope for the discovery of other S100B–effector protein
Acknowledgments
This work is supported by Hong Kong Baptist University (FRG2/17-18/003), the Health and Medical Research Fund (HMRF/14150561), the National Natural Science Foundation of China (21775131, China), the Hong Kong Baptist University Century Club Sponsorship Scheme 2019, the Interdisciplinary Research Matching Scheme (RC-IRMS/16-17/03), Interdisciplinary Research Clusters Matching Scheme (RC-IRCs/17-18/03), Collaborative Research Fund (C5026-16G), SKLEBA and HKBU Strategic Development Fund (
References (94)
- et al.
The S100 protein family
Trends Biochem. Sci.
(1988) S100B’s double life: intracellular regulator and extracellular signal
Biochim. Biophys. Acta Mol. Cell Res.
(2009)Complex formation between S100B protein and the p90 ribosomal S6 kinase (RSK) in malignant melanoma is calcium-dependent and inhibits extracellular signal-regulated kinase (ERK)-mediated phosphorylation of RSK
J. Biol. Chem.
(2014)A soluble protein characteristic of the nervous system
Biochem. Biophys. Res. Commun.
(1965)S100 protein family in human cancer
Am. J. Cancer Res.
(2014)S100B protein regulates astrocyte shape and migration via interaction with Src kinase implications for astrocyte development, activation, and tumor growth
J. Biol. Chem.
(2009)S100 protein: a marker for human malignant melanomas?
Lancet
(1981)The calcium-binding protein S100B down-regulates p53 and apoptosis in malignant melanoma
J. Biol. Chem.
(2010)Identification of small-molecule inhibitors of the human S100B–p53 interaction and evaluation of their activity in human melanoma cells
Bioorg. Med. Chem.
(2013)Current treatment strategies in elderly patients with metastatic colorectal cancer
Clin. Colorectal Cancer
(2007)
Treatment of brain metastases from lung cancer: chemotherapy
Lung Cancer
Prognostic value of serial blood S100B determinations in stage IIB–III melanoma patients: a corollary study to EORTC trial 18952
Eur. J. Cancer
Ovarian cancer
Lancet
Combination of ligand-and structure-based methods in virtual screening
Drug Discov. Today Technol.
De novo protein design: how do we expand into the universe of possible protein structures?
Curr. Med. Chem.
Recent progress in fragment-based lead discovery
Curr. Opin. Pharmacol.
Docking compared to 3D-pharmacophores: the scoring function challenge
Drug Discov. Today Technol.
Identification of potent urease inhibitors via ligand-and structure-based virtual screening and in vitro assays
J. Mol. Graph Model.
S100: a multigenic family of calcium-modulated proteins of the EF-hand type with intracellular and extracellular functional roles
Int. J. Biochem. Cell Biol.
The effects of CapZ peptide (TRTK-12) binding to S100B–Ca2+ as examined by NMR and X-ray crystallography
J. Mol. Biol.
Structure/function analysis of the interaction of phosphatidylinositol 4, 5-bisphosphate with actin-capping protein implications for how capping protein binds the actin filament
J. Biol. Chem.
Proteomics-based identification of spontaneous regression-associated proteins in neuroblastoma
J. Pediatr. Surg.
Characterization of S-100b binding epitopes. Identification of a novel target, the actin capping protein, CapZ
J. Biol. Chem.
A novel S100 target conformation is revealed by the solution structure of the Ca2+-S100B-TRTK-12 complex
J. Biol. Chem.
Recognition of the tumor suppressor protein p53 and other protein targets by the calcium-binding protein S100B
Biochim. Biophys. Acta
Structural basis of ribosomal S6 kinase 1 (RSK1) inhibition by S100B protein modulation of the extracellular signal-regulated kinase (Erk) signaling cascade in a calcium-dependent way
J. Biol. Chem.
S100B and S100A6 differentially modulate cell survival by interacting with distinct RAGE (receptor for advanced glycation end products) immunoglobulin domains
J. Biol. Chem.
The 1.5 Å crystal structure of human receptor for advanced glycation endproducts (RAGE) ectodomains reveals unique features determining ligand binding
J. Biol. Chem.
Divalent metal ion complexes of S100B in the absence and presence of pentamidine
J. Mol. Biol.
Solution NMR structure of S100B bound to the high-affinity target peptide TRTK-12
J. Mol. Biol.
Functions of S100 proteins
Curr. Mol. Med.
The evolution of S100B inhibitors for the treatment of malignant melanoma
Future Med. Chem.
A change-in-hand mechanism for S100 signalling
Biochem. Cell Biol.
Molecular mechanisms of S100‐target protein interactions
Microsc. Res. Tech.
S100B protein in the nervous system and cardiovascular apparatus in normal and pathological conditions
Cardiovasc. Psychiatry Neurol.
Structural basis for S100B interaction with its target proteins
J. Mol. Genet. Med.
Characterization of the tumor suppressor protein p53 as a protein kinase C substrate and a S100b-binding protein
Proc. Natl. Acad. Sci. U. S. A.
Covalent small molecule inhibitors of Ca2+-bound s100b
Biochemistry
Mimicking strategy for protein–protein interaction inhibitor discovery by virtual screening
Molecules
Prognostic value of the S100B protein in newly diagnosed and recurrent glioma patients: a serial analysis
J. Neuro-Oncol.
S100B promotes glioma growth through chemoattraction of myeloid-derived macrophages
Clin. Cancer Res.
S100B attenuates microglia activation in gliomas: possible role of STAT3 pathway
Glia
S100 protein is present in cultured human malignant melanomas
Nature
S100B expression in breast cancer as a predictive marker for cancer metastasis
Int. J. Oncol.
S100B promotes the proliferation, migration and invasion of specific brain metastatic lung adenocarcinoma cell line
Cell. Biol. Funct.
The effect of pentamidine on melanoma
Anticancer Drugs
Breast cancer metastasis: markers and models
Nat. Rev. Cancer
Cited by (8)
Unraveling the role of Xist RNA in cardiovascular pathogenesis
2024, Pathology Research and PracticeExosomal miRNA-mediated intercellular communications and immunomodulatory effects in tumor microenvironments
2023, Journal of Biomedical ScienceTime-Dependent Internalization of S100B by Mesenchymal Stem Cells via the Pathways of Clathrin- and Lipid Raft-Mediated Endocytosis
2021, Frontiers in Cell and Developmental Biology