Active β-catenin is regulated by the PTEN/PI3 kinase pathway: a role for protein phosphatase PP2A

Persad, A; Venkateswaran, Geetha; Li, Hao; Garcia, Maria Elizabeth; Yoon, Jenny; Sidhu, Jaskiran; Persad, Sujata

doi:10.18632/genesandcancer.128

Cited by 32 publications

(24 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition to the description of Wnt signaling above, the canonical Wnt pathway involves degradation of β-catenin by a β-TrCP1-containing E3 ligase, and alternative β-catenin degradation mediated by SIAH-1 (seven in absentia homolog-1) is responsible for the effect of CSN5 on β-catenin signaling 41 . Cross-talk occurs with other pathways including the PI3K/AKT 42 , 43 . Active β-catenin is induced by the PI3K pathway and is dependent on the phosphatase activity of the protein phosphatase PP2A 43 .…”

Section: Discussionmentioning

confidence: 99%

Cyclin D1-mediated microRNA expression signature predicts breast cancer outcome

Wang¹,

Gormley²,

Qiao³

et al. 2018

Theranostics

View full text Add to dashboard Cite

Background: Genetic classification of breast cancer based on the coding mRNA suggests the evolution of distinct subtypes. Whether the non-coding genome is altered concordantly with the coding genome and the mechanism by which the cell cycle directly controls the non-coding genome is poorly understood.Methods: Herein, the miRNA signature maintained by endogenous cyclin D1 in human breast cancer cells was defined. In order to determine the clinical significance of the cyclin D1-mediated miRNA signature, we defined a miRNA expression superset from 459 breast cancer samples. We compared the coding and non-coding genome of breast cancer subtypes.Results: Hierarchical clustering of human breast cancers defined four distinct miRNA clusters (G1-G4) associated with distinguishable relapse-free survival by Kaplan-Meier analysis. The cyclin D1-regulated miRNA signature included several oncomirs, was conserved in multiple breast cancer cell lines, was associated with the G2 tumor miRNA cluster, ERα+ status, better outcome and activation of the Wnt pathway. The coding and non-coding genome were discordant within breast cancer subtypes. Seed elements for cyclin D1-regulated miRNA were identified in 63 genes of the Wnt signaling pathway including DKK. Cyclin D1 restrained DKK1 via the 3'UTR. In vivo studies using inducible transgenics confirmed cyclin D1 induces Wnt-dependent gene expression.Conclusion: The non-coding genome defines breast cancer subtypes that are discordant with their coding genome subtype suggesting distinct evolutionary drivers within the tumors. Cyclin D1 orchestrates expression of a miRNA signature that induces Wnt/β-catenin signaling, therefore cyclin D1 serves both upstream and downstream of Wnt/β-catenin signaling.

show abstract

Section: Discussionmentioning

confidence: 99%

Cyclin D1-mediated microRNA expression signature predicts breast cancer outcome

Wang¹,

Gormley²,

Qiao³

et al. 2018

Theranostics

View full text Add to dashboard Cite

show abstract

“…A decrease of E-cadherin expression is closely related to tumor development, invasion and metastasis [ 41 ], and studies have shown that E-cadherin inhibits the Wnt/β-catenin pathway through its binding at the C-terminal domain of β-catenin at the plasma membrane, thereby sequestering β-catenin from the cytoplasmic pool [ 42 ]. β-Catenin is a crucial signaling molecule in the Wnt/β-catenin signaling pathway, and dephosphorylation of β-catenin at Ser33, Ser37, and Thr41 activates β-catenin [ 43 ]. C-myc is an important member of the proto-oncogene family that regulates cell proliferation, differentiation, and programmed cell death [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

Antitumor activity of resveratrol against human osteosarcoma cells: a key role of Cx43 and Wnt/β-catenin signaling pathway

et al. 2017

View full text Add to dashboard Cite

Osteosarcoma is a high-grade bone sarcoma with strong invasive ability. However, treatment with traditional chemotherapeutic drugs is limited by low tolerability and side effects. Resveratrol has been reported previously to have selective antitumor effect on various tumor cells while little is known about its effects and underlying mechanism in osteosarcoma biology. In this study, we found that resveratrol inhibits proliferation and glycolysis, induces apoptosis and reduces the invasiveness of U2-OS cells in vitro. After treatment with resveratrol, the expression of related Wnt/β-catenin signaling pathway target genes, such as β-catenin, c-myc, cyclin D1, MMP-2 and MMP-9, was downregulated and an increased E-cadherin level was observed as well. Additionally, the dual luciferase assay results also indicated that resveratrol suppressed the activity of Wnt/β-catenin signaling pathway. Interestingly, we noticed that the expression of connexin 43 (Cx43) increased with the prolongation of resveratrol treatment time. To further investigate the relationship between Cx43 and the Wnt/β-catenin signaling pathway in osteosarcoma, we used lentiviral-mediated shRNA to knockdown the expression of Cx43. Knockdown of Cx43 activated the Wnt/β-catenin signaling pathway, promoted proliferation and invasion, and inhibited apoptosis of U2-OS cells. Taken together, our results demonstrate that the antitumor activity of resveratrol against U2-OS cells in vitro occurs through up-regulating Cx43 and E-cadherin, and suppressing the Wnt/β-catenin signaling pathway. Moreover, Cx43 expression is negatively related to the activity of the Wnt/β-catenin pathway in U2-OS cells.

show abstract

“…Apart from different chemical inhibitors, many natural compounds have shown to target the Wnt pathway directly or indirectly. For example Indole-3-carbinol (I3C), a natural compound present in broccoli can inhibit WWS1-mediated proteasomal degradation of PTEN, which has a direct interaction with the Wnt/beta-catenin pathway, leading to tumor regression both in vitro and in vivo (119,120). Also, there are various repressor proteins reported to downregulate β-catenin.…”

Section: Hedgehog Inhibitorsmentioning

confidence: 99%

Wnt Signaling and Its Significance Within the Tumor Microenvironment: Novel Therapeutic Insights

et al. 2019

View full text Add to dashboard Cite

Wnt signaling is one of the central mechanisms regulating tissue morphogenesis during embryogenesis and repair. The pivot of this signaling cascade is the Wnt ligand, which binds to receptors belonging to the Frizzled family or the ROR1/ROR2 and RYK family. This interaction governs the downstream signaling cascade (canonical/non-canonical), ultimately extending its effect on the cellular cytoskeleton, transcriptional control of proliferation and differentiation, and organelle dynamics. Anomalous Wnt signaling has been associated with several cancers, the most prominent ones being colorectal, breast, lung, oral, cervical, and hematopoietic malignancies. It extends its effect on tumorigenesis by modulating the tumor microenvironment via fine crosstalk between transformed cells and infiltrating immune cells, such as leukocytes. This review is an attempt to highlight the latest developments in the understanding of Wnt signaling in the context of tumors and their microenvironment. A dynamic process known as immunoediting governs the fate of tumor progression based on the correlation of various signaling pathways in the tumor microenvironment and immune cells. Cancer cells also undergo a series of mutations in the tumor suppressor gene, which favors tumorigenesis. Wnt signaling, and its crosstalk with various immune cells, has both negative as well as positive effects on tumor progression. On one hand, it helps in the maintenance and renewal of the leucocytes. On the other hand, it promotes immune tolerance, limiting the antitumor response. Wnt signaling also plays a role in epithelial-mesenchymal transition (EMT), thereby promoting the maintenance of Cancer Stem Cells (CSCs). Furthermore, we have summarized the ongoing strategies used to target aberrant Wnt signaling as a novel therapeutic intervention to combat various cancers and their limitations.

show abstract

Active β-catenin is regulated by the PTEN/PI3 kinase pathway: a role for protein phosphatase PP2A

Cited by 32 publications

References 51 publications

Cyclin D1-mediated microRNA expression signature predicts breast cancer outcome

Cyclin D1-mediated microRNA expression signature predicts breast cancer outcome

Antitumor activity of resveratrol against human osteosarcoma cells: a key role of Cx43 and Wnt/β-catenin signaling pathway

Wnt Signaling and Its Significance Within the Tumor Microenvironment: Novel Therapeutic Insights

Contact Info

Product

Resources

About