Involvement of upregulation of fibronectin in the pro‑adhesive and pro‑survival effects of glucocorticoid on melanoma cells

Abstract

Glucocorticoids (GCs) are important stress hormones, which are used as a concomitant medication during malignant tumor chemotherapy. Clinical and preclinical studies have linked GCs to melanoma growth and progression. However, the effects and mechanism of action of GCs on the adhesion and survival of melanoma cells are still unknown. In the present study the effect of dexamethasone (Dex), a synthetic GC, on fibronectin (FN) expression and its roles in regulating the adhesion and survival of melanoma cells were investigated. It was revealed that Dex significantly increased the levels of intracellular and secreted FN in melanoma cell lines by increasing glucocorticoid receptor‑mediated FN protein stability. Additionally, it was demonstrated that Dex (100 nM) significantly promoted the adhesion and survival of melanoma cells. Silencing FN expression abrogated the pro‑adhesive and pro‑survival effects of Dex in melanoma cells. Extracellular FN significantly enhanced melanoma cell adhesion and survival in the presence of cisplatin, whereas partially blocking extracellular FN signaling with a CD44 antibody significantly reduced FN‑enhanced adhesion and survival. This indicated that the upregulation of FN contributed to the pro‑survival effect of Dex by enhancing cell adhesion. It was also observed that activation of the PI3K/AKT signaling pathway by extracellular FN was involved in the FN‑mediated increase in melanoma cell survival. These findings increase understanding of the possible mechanisms by which GCs regulate melanoma cell adhesion and survival.

Cell-intrinsic platinum response and associated genetic and gene expression signatures in ovarian cancer cell lines and isogenic models

“…While CCL5 is generally a chemoattractant to recruit immune cells, it has been implicated in ovarian cancer resistance through activation of pathways in cells directly, either through local secretion that causes STAT2 and PI3K/Akt activation 44 or through activation subsequent to BRCA1 inactivation which can lead to STING activation to promote inflammation 45 . FN1 is a fibronectin glycoprotein that has been implicated in inducing cisplatin resistance and correlating with patient outcome in ovarian and other cancers [46][47][48][49] . CD70 is a TNF-family cytokine that is typically found on activated T and B cells, but is known to be overexpressed in platinum-resistant A2780 cells 50 and is associated with poor survival and chemoresistance 51 .…”

CD44 and its implication in neoplastic diseases

“… 185 Additionally, by using a CD44 antibody to partially inhibit extracellular FN signaling, a significantly decrease in adhesion and survival of melanoma cells was obversed. 186 Furthermore, FN type III domain‐containing protein 3B circular RNA increased migration and invasion in GC with a decline in CD44. 187 Although there are few studies on regulating the interaction of CD44 with FN to treat cancer, owing to the key role of FN in cell migration and adhesion, this aspect may be a promising therapeutic strategy in cancer metastasis.…”

“…In endothelial cells, space microgravity was found to modulate the expression of CD44 and restrain collagen I and FN deposition, which involved cellular adhesion 185 . Additionally, by using a CD44 antibody to partially inhibit extracellular FN signaling, a significantly decrease in adhesion and survival of melanoma cells was obversed 186 . Furthermore, FN type III domain‐containing protein 3B circular RNA increased migration and invasion in GC with a decline in CD44 187 .…”