Ion, apoptosis, and cancer (71, 72). Insulin and IGF-1 binding to their receptors activates IRS proteins major to activation of PI3KAkt or MAPKERK12 cell signaling pathways, which play a role inside the standard development andFrontiers in Endocrinology | www.frontiersin.orgNovember 2017 | Volume eight | ArticleDalton et al.New Insights into the Mechanism of Action of sKlmaintenance of tissues. Dysregulation of those pathways can lead to tumor improvement and progression. -Klotho acts as a tumor suppressor by inhibiting insulinIGF-1 signaling in breast cancer, lung cancer, pancreatic cancer, gastric cancer, liver cancer, colon cancer, and ovarian cancer (57, 59, 65, 736). A2764 Autophagy Overexpression of -Klotho or treatment with sKl inhibits insulinIGF-1-mediated downstream effectors IRS-1, Akt1, and ERK12 in cancer cells (57, 59, 65, 67, 736). The tumor suppressive activity has been attributed to its KL1 domain (59, 76). Defects in the regulation of the Wnt signaling pathway also result in cancer (77). Wnt signaling is initiated when secreted Wnt ligands activate transmembrane receptors that promote the translocation of -catenin for the nucleus where it induces the activity of transcription components which include TCF and LEF (77). The activation of gene transcription by -catenin results in the synthesis of genes, such as c-myc and cyclin D1, that cause cancer cell growth and invasiveness (78). sKl is often a Wnt antagonist that binds to many Wnt ligands and inhibits their activation of Wnt signaling (79). sKl inhibition of the Wnt signaling pathway has been shown to decrease cancer cell invasiveness, proliferation, and viability, while it improved cancer cell apoptosis (60, 64, 80). Biochemical proof has shown that sKl reduces Wnt5A and Wnt3A expression and internalization in melanoma and lung cancer cells, which downregulates Wntcatenin signaling and expression from the Wnt target genes c-myc and cyclin D1 (60, 64). In melanoma cells, sKl lowered cell invasiveness by inhibiting Wnt5A stimulation of -calpain-mediated cleavage of Filamin A (60). TGF-1 signaling pathway plays an important part in cancer metastasis (81), and sKl suppressed TGF-1-induced epithelial-to-mesenchymal transition to inhibit renal fibrosis and cancer metastasis in mice (82). In vitro research revealed sKl binds the kind II TGF- receptor to lessen TGF-1 binding which inhibited receptor activation, Smad3 phosphorylation, and Smad3 transcriptional activity (82). Lastly, -Klotho acts as a tumor suppressor by modulating the FGF signaling pathway. Simple FGF-mediated ERK12 phosphorylation and activation on the FGF pathway inhibit colony formation in breast cancer cells (57). Overexpression of -Klotho enhanced bFGF-mediated ERK12 phosphorylation and FGF pathway activation in these cells (57). In pancreatic cancer cells, overexpression of -Klotho or the -Klotho KL1 domain decreased bFGF-mediated phosphorylation of Akt and ERK12 and cancer cell growth (59).identification of Membrane Lipid Rafts and Gangliosides As Receptors for sKlAs a “hormone,” sKl regulates several signaling pathways to elicit pleiotropic cellular effects. Having said that, the mechanism of action of hormonal sKl remains poorly understood in part Metolachlor medchemexpress because membrane receptors for sKl have not been identified. Current research have shed light on this gap in information and identified monosialogangliosides GM1 and GM3 present in lipid rafts as receptors for sKl (83). sKl co-migrated with lipid raft fractions in sucrose gradient ultracentrifugation experiments.
