TGFβ-Mediated Suppression of CD248 in Non-Cancer Cells Via Canonical Smad-Dependent Signaling Pathways is Uncoupled in Cancer Cells

Abstract

Wnt5a is classified as a non-transforming Wnt family member and plays complicated roles in oncogenesis and cancer metastasis. However, Wnt5a signaling in osteosarcoma progression remains poorly defined. In this study, we found that Wnt5a stimulated the migration of human osteosarcoma cells , with the maximal effect at 100 ng/ml, via enhancing phosphorylation of phosphatidylinositol-3 kinase (PI3K)/Akt. PI3K and Akt showed visible signs of basal phosphorylation and elevated phosphorylation at 15 min after stimulation with Wnt5a. Pharmaceutical inhibition of PI3K with LY294002 significantly blocked the Wnt5a-induced activation of Akt (p-Ser473) and decreased Wnt5a-induced cell migration. Akt siRNA remarkably inhibited Wnt5a-induced cell migration. Additionally, Wnt5a does not alter the total expression and phosphorylation of β-catenin in MG-63 cells. Taken together, we demonstrated for the first time that Wnt5a promoted osteosarcoma cell migration via the PI3K/Akt signaling pathway. These findings could provide a rationale for designing new therapy targeting osteosarcoma metastasis.

Deletion of Wnt5a in osteoclasts results in bone loss through decreased bone formation

“…9,11,12 Beyond the potential effects on osteoblastogenesis, the bone loss phenotype observed in Wnt5a cKO mice may also stem from impaired migration of mesenchymal stem cells to sites of bone resorption. Considering the established role of WNT5A in regulating migration of a variety of cell types, [42][43][44][45] researchers hypothesize that removal of Wnt5a from osteoclasts may also disrupt the dynamics of the BMU by interfering with the orderly genesis and migration of osteoblasts to sites of bone resorption. Our dynamic histomorphometry results support this idea since the MAR was not affected by Wnt5a cKO, suggesting that osteoblast number rather than osteoblast function is influenced by Wnt5a deletion in osteoclasts.…”

Alantolactone suppresses human osteosarcoma through the PI3K/AKT signaling pathway

“…accumulating evidence has indicated an important role of the Pi3K/aKT signaling pathway in osteosarcoma (11,34,35); Pi3K/aKT signaling modulates the proliferation, invasion, migration and apoptosis of osteosarcoma cell lines (36)(37)(38)(39)60). Previous studies revealed that alantolactone is a specific inhibitor in several diseases via the Pi3K/aKT signaling pathway (7,8).…”

“…Previous studies have reported that the Pi3K/aKT signaling pathway serves an important role in osteosarcoma (11,34,35); Pi3K/aKT modulates the proliferation, invasion, migration and apoptosis of osteosarcoma cell lines (36)(37)(38)(39). Thus, the effect of alT on the Pi3K/aKT signaling pathway was investigated to confirm whether it is the mechanism by which ALT affects osteosarcoma cells.…”

Wnt5a Induces Collagen Production by Human Periodontal Ligament Cells Through TGFβ1-Mediated Upregulation of Periostin Expression

“…ERK and JNK are important signaling molecules that influence cell proliferation (Osaki and Gama, 2013), and PI3K/AKT are also known to play a pivotal role in cell proliferation, migration and survival (Osaki et al, 2004;Shimabukuro et al, 2011). Wnt5a was shown to activate p42/44 MAPK, JNK, and AKT signal pathways in human dental papilla cells, indicating the involvement of Wnt5a in regulating cellular processes (Peng et al, 2010), and promote osteosarcoma cell migration via the PI3K/AKT signaling pathway (Zhang et al, 2014). As the phosphorylation of ERK, JNK, and AKT in HPDLCs was observed at 5 min after the onset of Wnt5a treatment in this study, Wnt5a may directly activate the MAPK signaling pathway, the Wnt/PCP pathway, and PI3K/AKT pathway responsible for various cellular processes such as cell proliferation and migration in PDL cells.…”