Role of Fibroblast Growth Factor 23 (FGF23) and αKlotho in Cancer

Abstract

Together with fibroblast growth factors (FGFs) 19 and 21, FGF23 is an endocrine member of the family of FGFs. Mainly secreted by bone cells, FGF23 acts as a hormone on the kidney, stimulating phosphate excretion and suppressing formation of 1,25(OH)2D3, active vitamin D. These effects are dependent on transmembrane protein αKlotho, which enhances the binding affinity of FGF23 for FGF receptors (FGFR). Locally produced FGF23 in other tissues including liver or heart exerts further paracrine effects without involvement of αKlotho. Soluble Klotho (sKL) is an endocrine factor that is cleaved off of transmembrane Klotho or generated by alternative splicing and regulates membrane channels, transporters, and intracellular signaling including insulin growth factor 1 (IGF-1) and Wnt pathways, signaling cascades highly relevant for tumor progression. In mice, lack of FGF23 or αKlotho results in derangement of phosphate metabolism and a syndrome of rapid aging with abnormalities affecting most organs and a very short life span. Conversely, overexpression of anti-aging factor αKlotho results in a profound elongation of life span. Accumulating evidence suggests a major role of αKlotho as a tumor suppressor, at least in part by inhibiting IGF-1 and Wnt/β-catenin signaling. Hence, in many malignancies, higher αKlotho expression or activity is associated with a more favorable outcome. Moreover, also FGF23 and phosphate have been revealed to be factors relevant in cancer. FGF23 is particularly significant for those forms of cancer primarily affecting bone (e.g., multiple myeloma) or characterized by bone metastasis. This review summarizes the current knowledge of the significance of FGF23 and αKlotho for tumor cell signaling, biology, and clinically relevant parameters in different forms of cancer.

Effect of Oxidative Stress-Induced Apoptosis on Active FGF23 Levels in MLO-Y4 Cells: The Protective Role of 17-β-Estradiol

“…The main target organ of FGF23 activity is the kidney, through its signaling receptor and co-receptor α-Klotho in the proximal renal tubules [5]. FGF23 down-regulates the expression of the sodium phosphate cotransporter, stimulating the release of Pi in the urine, and preventing the 1α-hydroxylation of 25-hydroxyvitamin D (25-(OH)D) with consequent decrease in the absorption of calcium and Pi by the intestine [6]. Altogether these changes cause decrease of blood Pi and 1-25-(OH)D levels, and consequently the activation of FGF23 secretion both in vivo and in vitro [7,8].…”

The regulation of FGF23 under physiological and pathophysiological conditions

“…Further malignancies found to exhibit, at least in part, higher FGF23 levels are ovarian cancer [ 101 ], prostate cancer [ 42 ], and multiple myeloma [ 99 ]. For further review, see [ 31 ].…”

Molecular Mechanisms and Biomarkers Associated with Chemotherapy-Induced AKI

“…FGF-23 is a crucial modulator of calcium and phosphate metabolism. In vitro, FGF-23 is overexpressed in osteoblast-like cells exposed to chemotherapeutics [ 38 ], while it has been established that FGF-23 may be upregulated in some cancers [ 39 ]. Together, this data indicates an interplay between FGF-23, AKI, and chemotherapy administration that should be further investigated.…”