Antagonistic role of Klotho-derived peptides dynamics in the pancreatic cancer treatment through obstructing WNT-1 and Frizzled binding

Fakhar, Muhammad; Najumuddin,; Gul, Mehreen; Rashid, Sajid

doi:10.1016/j.bpc.2018.07.002

Cited by 16 publications

(11 citation statements)

References 47 publications

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“…In a cell culture model, Wnt-Klotho interaction resulted in suppression of Wnt biological activity. In one plausible mechanism for the inhibitory effect of Klotho on Wnt signaling, Klotho binds to various Wnt family members and facilitates the closed-to open-state conformation of the Wnt-specific receptor FZD's cysteine-rich domain binding cavity, resulting in the loss of FZD binding (63). Alternatively, Wnt5a is bound to the cell surface by heparan sulfate proteoglycans, leading to the activation of Wnt signaling, but Klotho, which has sialidase activity, cleaves Wnt5a from the proteoglycans, such that it cannot be internalized and signal (64,65).…”

Section: Discussionmentioning

confidence: 99%

Salt causes aging-associated hypertension via vascular Wnt5a under Klotho deficiency

Kawarazaki¹,

Mizuno²,

Nishimoto³

et al. 2020

Journal of Clinical Investigation

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Section: Discussionmentioning

confidence: 99%

Salt causes aging-associated hypertension via vascular Wnt5a under Klotho deficiency

Kawarazaki¹,

Mizuno²,

Nishimoto³

et al. 2020

Journal of Clinical Investigation

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“…Besides, HIF-2α transcribes and maintains the levels of β-catenin and Smad4 in pancreatic tumors cells [40]. In comparison to normal, pancreatic cancer tissues have decreased levels of Fbxw7 [41], merlin [42], and klotho [43], which all suppress β-catenin levels, resulting in elevated β-catenin levels and activity. Proteasomal degradation of β-catenin is regulated by its phosphorylation and ubiquitination.…”

Section: Wnt/β-catenin Signaling In Pancreatic Cancermentioning

confidence: 99%

Wnt/β-Catenin Signaling: The Culprit in Pancreatic Carcinogenesis and Therapeutic Resistance

Makena

Gatla²,

Verlekar

et al. 2019

IJMS

118

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Pancreatic ductal adenocarcinoma (PDAC) is responsible for 7.3% of all cancer deaths. Even though there is a steady increase in patient survival for most cancers over the decades, the patient survival rate for pancreatic cancer remains low with current therapeutic strategies. The Wnt/β-catenin pathway controls the maintenance of somatic stem cells in many tissues and organs and is implicated in pancreatic carcinogenesis by regulating cell cycle progression, apoptosis, epithelial-mesenchymal transition (EMT), angiogenesis, stemness, tumor immune microenvironment, etc. Further, dysregulated Wnt has been shown to cause drug resistance in pancreatic cancer. Although different Wnt antagonists are effective in pancreatic patients, limitations remain that must be overcome to increase the survival benefits associated with this emerging therapy. In this review, we have summarized the role of Wnt signaling in pancreatic cancer and suggested future directions to enhance the survival of pancreatic cancer patients.

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“… 5 As an anti-tumor protein, Klotho is considered as a major factor underlying the pathogenesis of several cancers, such as breast cancer, 6 colorectal cancer, 7 and pancreatic cancer. 8 Klotho acts as a circulating hormone that inhibits cancer cell proliferation and migration by regulating tumor-related signal pathways, such as the Wnt/β-catenin and phosphoinositide 3-kinase (PI3K)/Akt pathways. 9 In highly malignant thyroid cancers, α-Klotho expression was negative or very weak.…”

Section: Introductionmentioning

confidence: 99%

Klotho Inhibits Proliferation in a RET Fusion Model of Papillary Thyroid Cancer by Regulating the Wnt/β-Catenin Pathway

Wu¹,

Jiang²,

Wu³

et al. 2021

CMAR

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Purpose We aimed to investigate the mechanisms of action on Klotho that underlie cancer development in RET fusion models of human papillary thyroid cancer (PTC). Materials and Methods Normal Nthy-ori 3-1 thyroid cells and two PTC cell lines (BHP10-3 and TPC-1), which were used as RET fusion models of PTC, were used to study Klotho. Klotho expression was analyzed by Western blotting. Klotho overexpression cell lines were constructed using the two types of PTC cells. Cell proliferation and apoptosis were assessed. Western blotting was used to detect the expression of proteins in the Wnt/β-catenin pathway. In addition, an activator and an inhibitor of the Wnt/β-catenin pathway were used to confirm that Klotho regulates the pathway in PTC cells. Mice were used to analyze the in vivo effect of Klotho on tumor growth and the Wnt/β-catenin pathway. Results In BHP10-3 and TPC-1 cells, Klotho expression was low. After Klotho overexpression, the cell proliferation was significantly suppressed and apoptosis was significantly increased (p<0.05). Wnt1, β-catenin, and CyclinD1 expression were also significantly decreased after Klotho overexpression (p<0.05). Administration of the Wnt/β-catenin pathway activator attenuated the effect of Klotho overexpression (p<0.05). In vivo, the tumor growth was suppressed, and apoptosis of the cancer cells in the tumors were increased after Klotho overexpression. However, injection of the Wnt/β-catenin pathway activator attenuated the effects of Klotho overexpression. Conclusion Klotho inhibits cell proliferation in RET fusion models of PTC by inhibiting the Wnt/β-catenin pathway, providing a potential target for developing treatment for PTC.

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Antagonistic role of Klotho-derived peptides dynamics in the pancreatic cancer treatment through obstructing WNT-1 and Frizzled binding

Cited by 16 publications

References 47 publications

Salt causes aging-associated hypertension via vascular Wnt5a under Klotho deficiency

Salt causes aging-associated hypertension via vascular Wnt5a under Klotho deficiency

Wnt/β-Catenin Signaling: The Culprit in Pancreatic Carcinogenesis and Therapeutic Resistance

Klotho Inhibits Proliferation in a RET Fusion Model of Papillary Thyroid Cancer by Regulating the Wnt/β-Catenin Pathway

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