Friend or Foe: S100 Proteins in Cancer

Allgöwer, Chantal; Kretz, Anna-Laura; Karstedt, Silvia von; Wittau, Mathias; Henne‐Bruns, Doris; Lemke, Johannes

doi:10.3390/cancers12082037

Cited by 92 publications

(95 citation statements)

References 266 publications

(355 reference statements)

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“…Since S100P binding lowers IFN-β cytotoxicity to MCF-7 breast cancer cells [ 30 ], S100P inhibition could promote enhancement of anticancer activity of IFN-β. Meanwhile, S100 protein family contains 25 cytosolic/nuclear/extracellular structurally homologous, but functionally diverse, Ca 2+ -binding proteins of the EF-hand superfamily, some of which also bind Zn 2+ /Cu 2+ /Fe 2+ [ 32 , 33 , 34 ]. S100 proteins exhibit tissue-specific expression profiles and broad functional repertoire, affected by their metal-binding, posttranslational modifications, oligomerization, and interaction with a wide spectrum of targets.…”

Section: Introductionmentioning

confidence: 99%

Interferon Beta Activity Is Modulated via Binding of Specific S100 Proteins

Kazakov

Sofin

Avkhacheva

et al. 2020

IJMS

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Interferon-β (IFN-β) is a pleiotropic cytokine used for therapy of multiple sclerosis, which is also effective in suppression of viral and bacterial infections and cancer. Recently, we reported a highly specific interaction between IFN-β and S100P lowering IFN-β cytotoxicity to cancer cells (Int J Biol Macromol. 2020; 143: 633–639). S100P is a member of large family of multifunctional Ca2+-binding proteins with cytokine-like activities. To probe selectivity of IFN-β—S100 interaction with respect to S100 proteins, we used surface plasmon resonance spectroscopy, chemical crosslinking, and crystal violet assay. Among the thirteen S100 proteins studied S100A1, S100A4, and S100A6 proteins exhibit strictly Ca2+-dependent binding to IFN-β with equilibrium dissociation constants, Kd, of 0.04–1.5 µM for their Ca2+-bound homodimeric forms. Calcium depletion abolishes the S100—IFN-β interactions. Monomerization of S100A1/A4/A6 decreases Kd values down to 0.11–1.0 nM. Interferon-α is unable of binding to the S100 proteins studied. S100A1/A4 proteins inhibit IFN-β-induced suppression of MCF-7 cells viability. The revealed direct influence of specific S100 proteins on IFN-β activity uncovers a novel regulatory role of particular S100 proteins, and opens up novel approaches to enhancement of therapeutic efficacy of IFN-β.

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Section: Introductionmentioning

confidence: 99%

Interferon Beta Activity Is Modulated via Binding of Specific S100 Proteins

Kazakov

Sofin

Avkhacheva

et al. 2020

IJMS

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“…Beyond serving as intracellular Ca2+ sensors, S100 proteins function as cytokine-like extracellular factors, thereby impacting on a number of biological functions [37]. Dysregulated expression of S100 proteins may occur in human cancers, therefore their use for predictive and prognostic purposes has been proposed [38]. The protein S100A7, also named psoriasin, was firstly identified as the most highly secreted protein in abnormally differentiated keratinocytes from psoriatic skin lesions, where S100A7 propagate aberrant immune and inflammatory signals [39,40].…”

Section: Discussionmentioning

confidence: 99%

Activation of the S100A7/RAGE Pathway by IGF-1 Contributes to Angiogenesis in Breast Cancer

Muoio

Talia

Lappano

et al. 2021

Cancers

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Background: Breast cancer (BC) mortality is increased among obese and diabetic patients. Both obesity and diabetes are associated with dysregulation of both the IGF-1R and the RAGE (Receptor for Advanced Glycation End Products) pathways, which contribute to complications of these disorders. The alarmin S100A7, signaling through the receptor RAGE, prompts angiogenesis, inflammation, and BC progression. Methods: We performed bioinformatic analysis of BC gene expression datasets from published studies. We then used Estrogen Receptor (ER)-positive BC cells, CRISPR-mediated IGF-1R KO BC cells, and isogenic S100A7-transduced BC cells to investigate the role of IGF-1/IGF-1R in the regulation of S100A7 expression and tumor angiogenesis. To this aim, we also used gene silencing and pharmacological inhibitors, and we performed gene expression and promoter studies, western blotting analysis, ChIP and ELISA assays, endothelial cell proliferation and tube formation assay. Results: S100A7 expression correlates with worse prognostic outcomes in human BCs. In BC cells, the IGF-1/IGF-1R signaling engages STAT3 activation and its recruitment to the S100A7 promoter toward S100A7 increase. In human vascular endothelial cells, S100A7 activates RAGE signaling and prompts angiogenic effects. Conclusions: In ER-positive BCs the IGF-1 dependent activation of the S100A7/RAGE signaling in adjacent endothelial cells may serve as a previously unidentified angiocrine effector. Targeting S100A7 may pave the way for a better control of BC, particularly in conditions of unopposed activation of the IGF-1/IGF-1R axis.

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“…Calmodulin antagonists have been shown to overcome resistance to TRAIL-based therapy in triple-negative breast cancer [ 50 ]. Several S100 proteins are differentially expressed in breast cancer tissue compared with normal tissue [ 51 ], suggesting that these proteins may be important in tumor development and progression [ 52 , 53 ]. High expression of S100A8 and S100A14 was associated with poor survival and higher incidence in breast cancer patients [ 32 , 54 ].…”

Section: Discussionmentioning

confidence: 99%

Modulation of calcium-binding proteins expression and cisplatin chemosensitivity by calcium chelation in human breast cancer MCF-7 cells

Hodeify

Siddiqui

Matar

et al. 2021

Heliyon

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Cisplatin (CDDP) is currently one of the most effective FDA-approved treatments for breast cancer. Previous studies have shown that CDDP-induced cell death in human breast cancer (MCF-7) cells is associated with disruption of calcium homeostasis. However, whether the sensitivity of breast cancer cells to cisplatin is associated with dysregulation of the expression of calcium-binding proteins (CaBPs) remains unknown. In this study, we evaluated the effect of the intracellular calcium chelator (BAPTA-AM) on viability of MCF-7 cells in the presence of toxic and sub-toxic doses of cisplatin. Furthermore, this study assessed the expression of CaBPs, calmodulin, S100A8, and S100A14 in MCF-7 cells treated with cisplatin. Cell viability was determined using MTT-based in vitro toxicity assay. Intracellular calcium imaging was done using Fluo-4 AM, a cell-permeant fluorescent calcium indicator. Expression of CaBPs was tested using real-time quantitative PCR. Exposure of cells to increasing amounts of CDDP correlated with increasing fluorescence of the intracellular calcium indicator, Fluo-4 AM. Conversely, treating cells with cisplatin significantly decreased mRNA levels of calmodulin, S100A8, and S100A14. Treatment of the cells with calcium chelator, BAPTA-AM, significantly enhanced the cytotoxic effects of sub-toxic dose of cisplatin. Our results indicated a statistically significant negative correlation between calmodulin, S100A8, and S100A14 expression and sensitivity of breast cancer cells to a sub-toxic dose of cisplatin. We propose that modulating the activity of calcium-binding proteins, calmodulin, S100A8, and S100A14, could be used to increase cisplatin efficacy, lowering its treatment dosage while maintaining its chemotherapeutic value.

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Friend or Foe: S100 Proteins in Cancer

Cited by 92 publications

References 266 publications

Interferon Beta Activity Is Modulated via Binding of Specific S100 Proteins

Interferon Beta Activity Is Modulated via Binding of Specific S100 Proteins

Activation of the S100A7/RAGE Pathway by IGF-1 Contributes to Angiogenesis in Breast Cancer

Modulation of calcium-binding proteins expression and cisplatin chemosensitivity by calcium chelation in human breast cancer MCF-7 cells

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