Complexity of the Wnt/β‑catenin pathway: Searching for an activation model

Tortelote, Giovane G.; Reis, Renata Rodrigues dos; Mendes, Fábio A.; Abreu, José G.

doi:10.1016/j.cellsig.2017.08.008

Cited by 63 publications

(57 citation statements)

References 232 publications

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“…XAV939 may suppress the activity of TNKS and stabilize Axin levels, thereby blocking the accumulation of b-catenin in the cytoplasm [34,35]. b-Catenin, as the central effector, plays a key role in the Wnt/b-catenin signalling cascade [36], whether the canonical Wnt pathway is activated or does not depend on the stability of b-catenin in the cytosol [37]. In the absence of activated Wnt signalling, b-catenin is actively degraded to maintain a low level of b-catenin in the cytosol.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Wnt signalling pathway by XAV939 enhances radiosensitivity in human cervical cancer HeLa cells

Zhang

Gan

et al. 2020

Artificial Cells, Nanomedicine, and Biotechnology

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Cervical cancer is the second most common malignant tumour threatening women's health. In recent years, heavy-ion beam therapy is becoming a newly emerging therapeutic mean of cancer; however, radio-resistance and radiation-induced damage constitute the main obstacles for curative treatment of cervical cancer. Therefore, to identify the radiosensitizers is essential. Here, we investigated the effects of Wnt signalling pathway on the response of 12 C 6þ radiation in HeLa cells. XAV939, an inhibitor of Wnt signalling pathway, was added two hours before 12 C 6þ radiation. 12 C 6þ radiation inhibited the viability of HeLa cells in a time-dependent manner, and inhibiting Wnt signalling using XAV939 significantly intensified this stress. Meanwhile, 12 C 6þ radiation induced a significant increased cell apoptosis, G2/M phase arrest, and the number of c-H2AX foci. Supplementation with XAV939 significantly increased the effects induced by 12 C 6þ radiation alone. Combining XAV939 with 12 C 6þ irradiation, the expression of apoptotic genes (p53, Bax, Bcl-2) was significantly increased, while the expression of Wnt-related genes (Wnt3a, Wnt5a, b-catenin, cyclin D1 and c-Myc) was significantly decreased. Overall, these findings suggested that blockage of the Wnt/b-catenin pathway effectively sensitizes HeLa cells to 12 C 6þ irradiation, and it may be a potential therapeutic approach in terms of increasing the clinical efficacy of 12 C 6þ beams.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Wnt signalling pathway by XAV939 enhances radiosensitivity in human cervical cancer HeLa cells

Zhang

Gan

et al. 2020

Artificial Cells, Nanomedicine, and Biotechnology

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“…LRP5 is a key component of the LRP5/LRP6/Frizzled co-receptor group that acts as a Wnt receptor, which when activated stabilizes cytoplasmic β-catenin to potentiate its downstream signaling (MacDonald and He, Tortelote et al, 2017). LRP5 is also a member of the LRP family that functions as an endocytic receptor of LDL to mediate LDL internalization for intracellular processing via the endosomal/lysosomal system (Krieger and Herz, 1994, Herz et al, 2009, Tortelote et al, 2017.…”

Section: Discussionmentioning

confidence: 99%

“…LRPs have dual receptor roles: 1) LA-enriched LDL endocytosis and subsequent degradation (Spiteller and Spiteller, 2000); and 2) transduction of Wnt signals to activate β-catenin (Zhu et al, 2003, Tortelote et al, 2017. In their LDL-related role, LRPs recruit 12/15-LOX to the cell membrane to oxidize LDL .…”

Section: -Lox-1 Suppresses La Upregulation Of Lrp5 and Active β-Catmentioning

confidence: 99%

Suppression of membranous LRP5 recycling, WNT/β-catenin signaling, and colorectal tumorigenesis by 15-LOX-1 peroxidation of PI3P_linoleic acid

Liu

Zuo

Liu

et al. 2019

Preprint

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Aberrant Wnt/β-catenin activation is a major driver of colorectal cancer (CRC), which is typically initiated by APC mutations. Additional modifiable factors beyond APC mutations have been recognized to be important for further potentiation of aberrant β-catenin activation to promote colorectal tumorigenesis. These factors have yet to be clearly identified. Western-type diets are increasingly enriched in linoleic acid (LA). LA-enriched diet however promotes chemically-induced colorectal tumorigenesis in rodent models. Furthermore, the main metabolizing enzyme of LA, 15-lipoxygenase-1 (15-LOX-1), is transcriptionally silenced in CRC. Whether LA and 15-LOX-1 affect Wnt/β-catenin signaling to modulate colorectal tumorigenesis is poorly understood. Herein, we report that high dietary LA promoted colorectal tumorigenesis in mice with intestinally targeted APC mutation (Apc Δ580 ) by upregulating a Wnt receptor, LRP5 expression, and β-catenin activation. 15-LOX-1 transgenic expression in intestinal epithelial cells suppressed LRP5 expression, β-catenin activation and subsequently CRC in these mice. In particular, 15-LOX-1 peroxidation of LA in phosphatidylinositol-3-phosphates (PI3P_LA) into PI3P_13-HODE decreased PI3P binding to SNX17and LRP5, which inhibited LRP5 recycling from endosomes to the plasma membrane, thereby leading to an increase of LRP5 lysosomal degradation. Our findings demonstrate for the first time that 15-LOX-1 metabolism of LA in PI3P to regulate LRP5 membrane abundance is a modifiable factor of Wnt/β-catenin aberrant signaling that could be potentially therapeutically targeted to suppress colorectal tumorigenesis and progression.

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“…Not surprisingly, the Wnt/β‐catenin pathway is also subject to intense regulation . Within the CXXC‐type zinc‐finger protein family, CXXC4 has been shown to interact with Dvl, resulting in inhibition of β‐catenin signaling .…”

Section: Cxxc5 Functions As a Signaling Regulator And Mediatormentioning

confidence: 99%

“…56,57 Not surprisingly, the Wnt/β-catenin pathway is also subject to intense regulation. 54,55,58 Within the CXXC-type zinc-finger protein family, CXXC4 has been shown to interact with Dvl, resulting in inhibition of β-catenin signaling. 19,59,60 Similarly, CXXC5 is also able to inhibit β-catenin signaling by interacting with the PDZ domain of the…”

Section: Cxxc5 In Wnt/β-catenin Signalingmentioning

confidence: 99%

CXXC5: A novel regulator and coordinator of TGF‐β, BMP and Wnt signaling

Xiong

Wang

et al. 2018

J Cellular Molecular Medi

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CXXC5 is a member of the CXXC‐type zinc‐finger protein family. Proteins in this family play a pivotal role in epigenetic regulation by binding to unmethylated CpG islands in gene promoters through their characteristic CXXC domain. CXXC5 is a short protein (322 amino acids in length) that does not have any catalytic domain, but is able to bind to DNA and act as a transcription factor and epigenetic factor through protein‐protein interactions. Intriguingly, increasing evidence indicates that expression of the CXXC5 gene is controlled by multiple signaling pathways and a variety of transcription factors, positioning CXXC5 as an important signal integrator. In addition, CXXC5 is capable of regulating various signal transduction processes, including the TGF‐β, Wnt and ATM‐p53 pathways, thereby acting as a novel and crucial signaling coordinator. CXXC5 plays an important role in embryonic development and adult tissue homeostasis by regulating cell proliferation, differentiation and apoptosis. In keeping with these functions, aberrant expression or altered activity of CXXC5 has been shown to be involved in several human diseases including tumourigenesis. This review summarizes the current understanding of CXXC5 as a transcription factor and signaling regulator and coordinator.

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Complexity of the Wnt/β‑catenin pathway: Searching for an activation model

Cited by 63 publications

References 232 publications

Inhibition of Wnt signalling pathway by XAV939 enhances radiosensitivity in human cervical cancer HeLa cells

Inhibition of Wnt signalling pathway by XAV939 enhances radiosensitivity in human cervical cancer HeLa cells

Suppression of membranous LRP5 recycling, WNT/β-catenin signaling, and colorectal tumorigenesis by 15-LOX-1 peroxidation of PI3P_linoleic acid

CXXC5: A novel regulator and coordinator of TGF‐β, BMP and Wnt signaling

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