Klotho and the Treatment of Human Malignancies

Sachdeva, Aishani; Gouge, J.; Kontovounisios, Christos; Nikolaou, Stella; Ashworth, Alan; Lim, Kenneth; Chong, Irene

doi:10.3390/cancers12061665

Cited by 30 publications

(40 citation statements)

References 157 publications

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“…34 Additionally, recent evidence suggests that sleep deprivation and sleep disorders may lead to decreased concentrations of the circulating anti-aging protein Klotho, 35,36 which is a tumor suppressor and modulator of insulin-like growth factor-1 and other oncogenic signaling pathways. 37 obesity is associated with sleep apnoea and chronic intermittent hypoxia, which has been recognized as a promoter of multiple myeloma. 39 Shorter sleep duration in these settings may reduce the period of time spent under a chronic intermittent hypoxic state each night and may thus be protective for multiple myeloma risk.…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, sleep deprivation may indirectly, via insulin metabolism, affect circulating levels of insulin‐like growth factor‐1, which were positively associated with colorectal cancer in a previous MR study 34 . Additionally, recent evidence suggests that sleep deprivation and sleep disorders may lead to decreased concentrations of the circulating anti‐aging protein Klotho, 35,36 which is a tumor suppressor and modulator of insulin‐like growth factor‐1 and other oncogenic signaling pathways 37 38 which may predispose an individual to the development of gastrointestinal cancer.…”

Section: Discussionmentioning

confidence: 96%

See 1 more Smart Citation

Sleep duration and risk of overall and 22 site‐specific cancers: A Mendelian randomization study

Titova

Michaëlsson

Vithayathil

et al. 2020

Intl Journal of Cancer

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Studies of sleep duration in relation to the risk of site-specific cancers other than breast cancer are scarce. Furthermore, the available results are inconclusive and the causality remains unclear. We aimed to investigate the potential causal associations of sleep duration with overall and site-specific cancers using the Mendelian randomization (MR) design. Single-nucleotide polymorphisms associated with the sleep traits identified from a genome-wide association study were used as instrumental variables to estimate the association with overall cancer and 22 site-specific cancers among 367 586 UK Biobank participants. A replication analysis was performed using data from the FinnGen consortium (up to 121 579 individuals). There was suggestive evidence that genetic liability to short-sleep duration was associated with higher odds of

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 96%

Sleep duration and risk of overall and 22 site‐specific cancers: A Mendelian randomization study

Titova

Michaëlsson

Vithayathil

et al. 2020

Intl Journal of Cancer

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“…Cleavage of Klotho family members gives rise to a secreted and soluble version. Klotho in cancer is generally associated with being a tumor suppressor [ 247 ].…”

Section: The Role Of Canonical Fgfr Cofactors In Cancermentioning

confidence: 99%

Fibroblast Growth Factor Receptors (FGFRs) and Noncanonical Partners in Cancer Signaling

Ferguson

Smith

Francavilla

2021

Cells

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Increasing evidence indicates that success of targeted therapies in the treatment of cancer is context-dependent and is influenced by a complex crosstalk between signaling pathways and between cell types in the tumor. The Fibroblast Growth Factor (FGF)/FGF receptor (FGFR) signaling axis highlights the importance of such context-dependent signaling in cancer. Aberrant FGFR signaling has been characterized in almost all cancer types, most commonly non-small cell lung cancer (NSCLC), breast cancer, glioblastoma, prostate cancer and gastrointestinal cancer. This occurs primarily through amplification and over-expression of FGFR1 and FGFR2 resulting in ligand-independent activation. Mutations and translocations of FGFR1-4 are also identified in cancer. Canonical FGF-FGFR signaling is tightly regulated by ligand-receptor combinations as well as direct interactions with the FGFR coreceptors heparan sulfate proteoglycans (HSPGs) and Klotho. Noncanonical FGFR signaling partners have been implicated in differential regulation of FGFR signaling. FGFR directly interacts with cell adhesion molecules (CAMs) and extracellular matrix (ECM) proteins, contributing to invasive and migratory properties of cancer cells, whereas interactions with other receptor tyrosine kinases (RTKs) regulate angiogenic, resistance to therapy, and metastatic potential of cancer cells. The diversity in FGFR signaling partners supports a role for FGFR signaling in cancer, independent of genetic aberration.

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“…(B) Klotho (KL) is a tumor-suppressor inhibiting pathways relevant for tumorigenesis including IGF-1R, Wnt/β-catenin, and NF-κB signaling, resulting in decreased cell proliferation, invasion, migration, tumor growth, protein synthesis, and EMT and inducing apoptosis. Figure according to Sachdeva et al (2020) . Created with BioRender.com .…”

Section: Fgf23/kl and The Cancer Microenvironmentmentioning

confidence: 99%

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

Ewendt

Feger

Föller

2021

Front. Cell Dev. Biol.

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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.

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Klotho and the Treatment of Human Malignancies

Cited by 30 publications

References 157 publications

Sleep duration and risk of overall and 22 site‐specific cancers: A Mendelian randomization study

Sleep duration and risk of overall and 22 site‐specific cancers: A Mendelian randomization study

Fibroblast Growth Factor Receptors (FGFRs) and Noncanonical Partners in Cancer Signaling

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

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