WNT/β-catenin signaling regulates mitochondrial activity to alter the oncogenic potential of melanoma in a PTEN-dependent manner

Brown, Kate; Yang, Peter; Salvador, Daniela; Kulikauskas, Rima M.; Ruohola‐Baker, Hannele; Robitaille, Aaron M.; Chien, Andy J.; Moon, R T; Sherwood, Victoria

doi:10.1038/onc.2016.450

Cited by 54 publications

(53 citation statements)

References 103 publications

(136 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These observations suggest that there may be some exceptions to the benefits of dual therapy. Indeed, one recent report strongly suggests that PTEN status in BRAF -activated melanoma affects whether Wnt signaling promotes or suppresses metastasis (66). = Additional rigorous preclinical and clinical experimentation will be necessary to determine which genetic backgrounds are most sensitive to dual therapy in melanoma.…”

Section: Discussionmentioning

confidence: 99%

β-Catenin mRNA Silencing and MEK Inhibition Display Synergistic Efficacy in Preclinical Tumor Models

Ganesh

Shui

Craig

et al. 2018

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Colorectal carcinomas (CRC) harbor well-defined genetic abnormalities including aberrant activation of Wnt/β-catenin and MAPK pathways, often simultaneously. While the MAPK pathway can be targeted using potent small molecule drugs, including BRAF and MEK inhibitors, β-catenin inhibition has been historically challenging. RNA interference (RNAi) approaches have advanced to the stage of clinical viability, and are especially well-suited for transcriptional modulators such as β-catenin. In this study, we report therapeutic effects of combined targeting of these pathways with pharmacological agents. Using a recently-described tumor-selective nanoparticle containing a β-catenin-targeting RNAi trigger, in combination with the FDA-approved MEK inhibitor (MEKi) trametinib, we demonstrate synergistic tumor growth inhibition in in vivo models of CRC, melanoma and hepatocellular carcinoma. At dose levels which were insufficient to significantly impact tumor growth as monotherapies, combination regimens resulted in synergistic efficacy and complete tumor growth inhibition. Importantly, dual MEKi/RNAi therapy dramatically improved survival of mice bearing CRC liver metastases. In addition, pharmacological silencing of β-catenin mRNA was effective against tumors which are inherently resistant or which acquire drug-induced resistance to trametinib. These results provide a strong rationale for clinical evaluation of this dual-targeting approach for cancers harboring Wnt/β-catenin and MAPK pathway mutations.

show abstract

Section: Discussionmentioning

confidence: 99%

β-Catenin mRNA Silencing and MEK Inhibition Display Synergistic Efficacy in Preclinical Tumor Models

Ganesh

Shui

Craig

et al. 2018

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

show abstract

“…Thus, in the adult, Notch‐induced inhibition of fission might be involved in the reduced activation of DRP1 in SVZ‐OPCs . Furthermore, activation of Wnt/β‐catenin in tumour cells promotes aerobic glycolysis, and modulates mitochondrial dynamics by decreasing DRP1 interaction with mitochondria and increasing expression of mitofusin, a key player of mitochondrial dynamics . Since a crosstalk between THs and Wnt is well‐demonstrated in many stem cell types in several organisms, Wnt could be a key TH‐target pathway playing a role in mitochondria dependent NSC fate decision.…”

Section: Implications Of Cell Metabolism On Neurogenesis and Th‐inducmentioning

confidence: 99%

Thyroid hormone regulation of neural stem cell fate: From development to ageing

et al. 2019

View full text Add to dashboard Cite

In the vertebrate brain, neural stem cells (NSCs) generate both neuronal and glial cells throughout life. However, their neuro-and gliogenic capacity changes as a function of the developmental context. Despite the growing body of evidence on the variety of intrinsic and extrinsic factors regulating NSC physiology, their precise cellular and molecular actions are not fully determined. Our review focuses on thyroid hormone (TH), a vital component for both development and adult brain function that regulates NSC biology at all stages. First, we review comparative data to analyse how TH modulates neuro-and gliogenesis during vertebrate brain development. Second, as the mammalian brain is the most studied, we highlight the molecular mechanisms underlying TH action in this context. Lastly, we explore how the interplay between TH signalling and cell metabolism governs both neurodevelopmental and adult neurogenesis. We conclude that, together, TH and cellular metabolism regulate optimal brain formation, maturation and function from early foetal life to adult in vertebrate species. cell fate, development, evo-devo, metabolism, mitochondria, neural stem cell, thyroid hormone This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. K E Y W O R D S

show abstract

“…The transcriptional activity of NFAT transcriptional is increased by mitogen-activated protein kinase p38 during Wnt stimulation ( Matsumoto et al, 2017 ; Tan et al, 2018 ). In addition to the Ca 2+ -mediated signaling cascade, the induction of non-canonical Wnt signaling activates Rho-family small GTPases, including Cdc42, Rac, and RhoA, by recruiting the receptor/coreceptor/Dvl complex ( Brown et al, 2017 ).…”

Section: The Wnt/β-catenin Signaling Pathwaymentioning

confidence: 99%

Regulatory Mechanisms of the Wnt/β-Catenin Pathway in Diabetic Cutaneous Ulcers

et al. 2018

View full text Add to dashboard Cite

Skin ulcers are a serious complication of diabetes. Diabetic patients suffer from vascular lesions and complications such as peripheral neuritis, peripheral vascular lesions, and collagen abnormalities, which result in skin wounds that are refractory and often develop into chronic ulcers. The healing of skin ulcers requires an inflammatory reaction, wound proliferation, remodeling regulation, and control of stem cells. Studies investigating diabetic cutaneous ulcers have focused on cellular and molecular levels. Diabetes can cause nerve and blood vessel damage, and persistent high blood sugar levels can cause systemic multisite nerve damage based on peripheral neuropathy. The long-term hyperglycemia state enables the polyol glucose metabolism pathway to be activated, increasing the accumulation of toxic substances in the vascular injured nerve tissue cells. Sustained hyperglycemia leads to dysfunction of epithelial cells, leading to a decrease in pro-angiogenic signaling and nitric oxide production. In addition, due to impaired leukocyte function in hyperglycemia, immune function is impaired and the immune response at relevant sites is insufficient, making diabetic foot more difficult to heal. The Wnt/β-catenin pathway is a highly conserved signal transduction pathway involved in a variety of biological processes, such as cell proliferation, apoptosis, and differentiation. It is considered an important pathway involved in the healing of skin wounds. This article summarizes the mechanism of action of the Wnt/β-catenin pathway involved in the inflammatory responses to diabetic ulcers, wound proliferation, wound remodeling, and stem cells. The interactions between the Wnt signal pathway and other metabolic pathways are also discussed.

show abstract

WNT/β-catenin signaling regulates mitochondrial activity to alter the oncogenic potential of melanoma in a PTEN-dependent manner

Cited by 54 publications

References 103 publications

β-Catenin mRNA Silencing and MEK Inhibition Display Synergistic Efficacy in Preclinical Tumor Models

β-Catenin mRNA Silencing and MEK Inhibition Display Synergistic Efficacy in Preclinical Tumor Models

Thyroid hormone regulation of neural stem cell fate: From development to ageing

Regulatory Mechanisms of the Wnt/β-Catenin Pathway in Diabetic Cutaneous Ulcers

Contact Info

Product

Resources

About