IGFBP‐3 inhibits Wnt signaling in metastatic melanoma cells

Naspi, Antimo; Zingariello, Maria; Sancillo, Laura; Panasiti, Vincenzo; Polinari, Dorina; Martella, Marianna; Alba, Rana Rosa; Londei, Paola

doi:10.1002/mc.22525

Cited by 19 publications

(11 citation statements)

References 35 publications

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“…However, only the expression of p-GSK-3 β was decreased along with ILK in a dose-dependent manner, while p-Akt failed to participate in the process. It is well known that decrease of the expression of p-GSK-3 β led to the increase of GSK-3 β kinase activity, followed by phosphorylation of β -catenin [39, 40]. Similarly, our present results showed downregulated β -catenin after treatment with emodin.…”

Section: Discussionsupporting

confidence: 84%

Emodin Inhibits the Epithelial to Mesenchymal Transition of Epithelial Ovarian Cancer Cells via ILK/GSK-3β/Slug Signaling Pathway

Xuan

et al. 2016

BioMed Research International

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Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. Despite the anticancer capabilities of emodin observed in many cancers, including EOC, the underlying molecular mechanism remains to be elucidated. A crucial link has been discovered between the acquisition of metastatic traits and the epithelial-mesenchymal transition (EMT). The present study aimed to determine whether emodin could inhibit the EMT of EOC cells and explore the underlying mechanism. The CCK-8 assay and transwell assay showed that emodin effectively repressed the abilities of proliferation, invasion, and migration in A2780 and SK-OV-3 cells. The Western blot showed that emodin upregulated epithelial markers (E-cadherin and Claudin) while it downregulated mesenchymal markers (N-cadherin and Vimentin) and transcription factor (Slug) in a dose-dependent fashion. After transfection of siRNA-Slug, both Slug and N-cadherin were downregulated in EOC cells while E-cadherin was upregulated, which was intensified by emodin. Besides, emodin decreased the expression of ILK, p-GSK-3β, β-catenin, and Slug. Transfection of siRNA-ILK also achieved the same effects, which was further strengthened by following emodin treatment. Nevertheless, SB216763, an inhibitor of GSK-3β, could reverse the effects of emodin except for ILK expression. These findings suggest that emodin inhibited the EMT of EOC cells via ILK/GSK-3β/Slug signaling pathway.

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Section: Discussionsupporting

confidence: 84%

Emodin Inhibits the Epithelial to Mesenchymal Transition of Epithelial Ovarian Cancer Cells via ILK/GSK-3β/Slug Signaling Pathway

Xuan

et al. 2016

BioMed Research International

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“…Similarly, the activity of SERPINE2 stimulates the melanoma metastatic behaviour [ 73 ]. On the other hand, the role of the IGFBP3 gene in cancer is not entirely understood, because both melanoma-supporting and inhibiting effect was shown concerning this factor [ 74 , 75 ]. The activity of genes encoding E- and N-cadherins ( CDH1 , CDH2 ) was detected in melanoma cells prepared from the spheroids.…”

Section: Discussionmentioning

confidence: 99%

Single-Cell RNA Sequencing Unravels Heterogeneity of the Stromal Niche in Cutaneous Melanoma Heterogeneous Spheroids

Novotný

Strnadová

Dvořánková

et al. 2020

Cancers

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Heterogeneous spheroids have recently acquired a prominent position in melanoma research because they incorporate microenvironmental cues relevant for melanoma. In this study, we focused on the analysis of microenvironmental factors introduced in melanoma heterogeneous spheroids by different dermal fibroblasts. We aimed to map the fibroblast diversity resulting from previously acquired damage caused by exposure to extrinsic and intrinsic stimuli. To construct heterogeneous melanoma spheroids, we used normal dermal fibroblasts from the sun-protected skin of a juvenile donor. We compared them to the fibroblasts from the sun-exposed photodamaged skin of an adult donor. Further, we analysed the spheroids by single-cell RNA sequencing. To validate transcriptional data, we also compared the immunohistochemical analysis of heterogeneous spheroids to melanoma biopsies. We have distinguished three functional clusters in primary human fibroblasts from melanoma spheroids. These clusters differed in the expression of (a) extracellular matrix-related genes, (b) pro-inflammatory factors, and (c) TGFβ signalling superfamily. We observed a broader deregulation of gene transcription in previously photodamaged cells. We have confirmed that pro-inflammatory cytokine IL-6 significantly enhances melanoma invasion to the extracellular matrix in our model. This supports the opinion that the aspects of ageing are essential for reliable melanoma 3D modelling in vitro.

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“…Glycosylated recombinant His-tagged IGFBP-3 (Speed BioSystems) and nonglycosylated recombinant IGFBP-3 (MyBioSource, San Diego, CA, USA) were used as reported earlier [69]. Glycosylated human CD44 recombinant protein was purchased from Sino Biological (Wayne, PA, USA).…”

Section: Tcep-hcl Reduction and Deglycosylationmentioning

confidence: 99%

Biochemical determinants of the IGFBP‐3–hyaluronan interaction

et al. 2020

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IGFBP‐3, the most abundant IGFBP and the main carrier of insulin‐like growth factor I (IGF‐I) in the circulation, can bind IGF‐1 with high affinity, which attenuates IGF/IGF‐IR interactions, thereby resulting in antiproliferative effects. The C‐terminal domain of insulin‐like growth factor‐binding protein‐3 (IGFBP‐3) is known to contain an 18‐basic amino acid motif capable of interacting with either humanin (HN) or hyaluronan (HA). We previously showed that the 18‐amino acid IGFBP‐3 peptide is capable of binding either HA or HN with comparable affinities to the full‐length IGFBP‐3 protein and that IGFBP‐3 can compete with the HA receptor, CD44, for binding HA. Blocking the interaction between HA and CD44 reduced viability of A549 human lung cancer cells. In this study, we set out to better characterize IGFBP‐3‐HA interactions. We show that both stereochemistry and amino acid identity are important determinants of the interaction between the IGFBP‐3 peptide and HA and for the peptide's ability to exert its cytotoxic effects. Binding of IGFBP‐3 to either HA or HN was unaffected by glycosylation or reduction of IGFBP‐3, suggesting that the basic 18‐amino acid residue sequence of IGFBP‐3 remains accessible for interaction with either HN or HA upon glycosylation or reduction of the full‐length protein. Removing N‐linked oligosaccharides from CD44 increased its ability to compete with IGFBP‐3 for binding HA, while reduction of CD44 rendered the protein relatively ineffective at blocking IGFBP‐3‐HA interactions. We conclude that both deglycosylation and disulfide bond formation are important for CD44 to compete with IGFBP‐3 for binding HA.

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IGFBP‐3 inhibits Wnt signaling in metastatic melanoma cells

Cited by 19 publications

References 35 publications

Emodin Inhibits the Epithelial to Mesenchymal Transition of Epithelial Ovarian Cancer Cells via ILK/GSK-3β/Slug Signaling Pathway

Emodin Inhibits the Epithelial to Mesenchymal Transition of Epithelial Ovarian Cancer Cells via ILK/GSK-3β/Slug Signaling Pathway

Single-Cell RNA Sequencing Unravels Heterogeneity of the Stromal Niche in Cutaneous Melanoma Heterogeneous Spheroids

Biochemical determinants of the IGFBP‐3–hyaluronan interaction

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