Molecular Features of the YAP Inhibitor Verteporfin: Synthesis of Hexasubstituted Dipyrrins as Potential Inhibitors of YAP/TAZ, the Downstream Effectors of the Hippo Pathway

Gibault, Floriane; Bailly, Fabrice; Corvaisier, Matthieu; Coevoet, Mathilde; Huet, Guillemette; Melnyk, Patricia; Cotelle, Philippe

doi:10.1002/cmdc.201700063

Cited by 65 publications

(54 citation statements)

References 33 publications

(56 reference statements)

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“…Having demonstrated that blocking SPHK1 activity attenuates BLM-or TGF-β-mediated mtROS and the expression of FN and α-SMA, we investigated the effect of YAP1 inhibition, or the downregulation of YAP1, with shRNA on mtROS, FN, and α-SMA expression in lung fibroblasts. The HLFs were pre-treated with YAP1 inhibitor verteporfin (1 µ M) [45,46] for 1 h prior to the TGF-β (5 ng/mL) challenge for 3 h, and mtROS was determined by MitoSOX. The inhibition of YAP1 by verteporfin reduced the TGF-β-induced mtROS ( Figure 8A), suggesting a role for YAP1 in mtROS production.…”

Section: Inhibition or Downregulation Of Yap1 Reduces Tgf-β-induced Mmentioning

confidence: 99%

Sphingosine Kinase 1/S1P Signaling Contributes to Pulmonary Fibrosis by Activating Hippo/YAP Pathway and Mitochondrial Reactive Oxygen Species in Lung Fibroblasts

Huang

Sudhadevi

et al. 2020

IJMS

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The sphingosine kinase 1 (SPHK1)/sphingosine–1–phosphate (S1P) signaling axis is emerging as a key player in the development of idiopathic pulmonary fibrosis (IPF) and bleomycin (BLM)-induced lung fibrosis in mice. Recent evidence implicates the involvement of the Hippo/Yes-associated protein (YAP) 1 pathway in lung diseases, including IPF, but its plausible link to the SPHK1/S1P signaling pathway is unclear. Herein, we demonstrate the increased co-localization of YAP1 with the fibroblast marker FSP1 in the lung fibroblasts of BLM-challenged mice, and the genetic deletion of Sphk1 in mouse lung fibroblasts (MLFs) reduced YAP1 localization in fibrotic foci. The PF543 inhibition of SPHK1 activity in mice attenuated YAP1 co-localization with FSP1 in lung fibroblasts. In vitro, TGF-β stimulated YAP1 translocation to the nucleus in primary MLFs, and the deletion of Sphk1 or inhibition with PF543 attenuated TGF-β-mediated YAP1 nuclear localization. Moreover, the PF543 inhibition of SPHK1, or the verteporfin inhibition of YAP1, decreased the TGF-β- or BLM-induced mitochondrial reactive oxygen species (mtROS) in human lung fibroblasts (HLFs) and the expression of fibronectin (FN) and alpha-smooth muscle actin (α-SMA). Furthermore, scavenging mtROS with MitoTEMPO attenuated the TGF-β-induced expression of FN and α-SMA. The addition of the S1P antibody to HLFs reduced TGF-β- or S1P-mediated YAP1 activation, mtROS, and the expression of FN and α-SMA. These results suggest a role for SPHK1/S1P signaling in TGF-β-induced YAP1 activation and mtROS generation, resulting in fibroblast activation, a critical driver of pulmonary fibrosis.

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Section: Inhibition or Downregulation Of Yap1 Reduces Tgf-β-induced Mmentioning

confidence: 99%

Sphingosine Kinase 1/S1P Signaling Contributes to Pulmonary Fibrosis by Activating Hippo/YAP Pathway and Mitochondrial Reactive Oxygen Species in Lung Fibroblasts

Huang

Sudhadevi

et al. 2020

IJMS

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“…Verteporfin, a member of porphyrin family, is identified as the most effective inhibitory drug against YAP1-TEADs complex, and it is approved by Food and Drug Administration (FDA) for the treatment of macular degeneration. 5,96 Inhibition of YAP1 by genetic silencing or verteporfin can increase the sensitivity of cisplatin, erlotinib and gefitinib in different cancer types. 13,16,18,86 In addition to verteporfin, other drugs such as dasatinib and statins are capable of blocking YAP1/TAZ activities through the suppression of YAP1/TAZ associated components.…”

Section: Yap1 Signaling and Drug Resistancementioning

confidence: 99%

A time for YAP1: Tumorigenesis, immunosuppression and targeted therapy

Shibata

Ham

Hoque

2018

Intl Journal of Cancer

136

143

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YAP1 is one of the most important effectors of the Hippo pathway and has crosstalk with other cancer promoting pathways. YAP1 contributes to cancer development in various ways that include promoting malignant phenotypes, expansion of cancer stem cells and drug resistance of cancer cells. Because pharmacologic or genetic inhibition of YAP1 suppresses tumor progression and increases the drug sensitivity, targeting YAP1 may open a fertile avenue for a novel therapeutic approach in relevant cancers. Recent enormous studies have established the efficacy of immunotherapy, and several immune checkpoint blockades are in clinical use or in the phase of development to treat various cancer types. Immunosuppression in the tumor microenvironment (TME) induced by cancer cells, immune cells and associated stromal cells promotes tumor progression and causes drug resistance. Accumulated evidences of scientific efforts from the last few years suggest that YAP1 influences macrophages, myeloid-derived suppressor cells and regulatory T-cells to facilitate immunosuppressive TME. Although the underlying mechanisms is not clearly discerned, it is evident that YAP1 activating pathways in different cellular components induce immunosuppressive TME. In this review, we summarize the evidences involved in the dual roles of YAP1 in cancer development and immunosuppression in the TME. We also discuss the possibility of YAP1 as a novel therapeutic target.

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“…However, verteporfin’s promise as a YAP/TAZ-TEAD inhibitor is outweighed by high toxicity and the accounts of YAP/TAZ-TEAD independent effects [ 196 , 197 , 198 ]. Although verteporfin prevents YAP-TEAD activity by preventing YAP-TEAD interaction [ 104 ], other evidence shows it can also activate the Hippo pathway [ 191 ], and regulate YAP and TAZ protein expression [ 189 , 190 , 191 , 195 , 199 ]. This apparent lack of specificity further diminishes its therapeutic potential.…”

Section: Therapeutic Potential Of Targeting Yap/taz-tead In Cancermentioning

confidence: 99%

YAP/TAZ Activation as a Target for Treating Metastatic Cancer

Warren

Xiao

2018

Cancers

139

131

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Yes-Associated Protein (YAP) and Transcriptional Co-activator with PDZ-binding Motif (TAZ) have both emerged as important drivers of cancer progression and metastasis. YAP and TAZ are often upregulated or nuclear localized in aggressive human cancers. There is abundant experimental evidence demonstrating that YAP or TAZ activation promotes cancer formation, tumor progression, and metastasis. In this review we summarize the evidence linking YAP/TAZ activation to metastasis, and discuss the roles of YAP and TAZ during each step of the metastatic cascade. Collectively, this evidence strongly suggests that inappropriate YAP or TAZ activity plays a causal role in cancer, and that targeting aberrant YAP/TAZ activation is a promising strategy for the treatment of metastatic disease. To this end, we also discuss several potential strategies for inhibiting YAP/TAZ activation in cancer and the challenges each strategy poses.

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Molecular Features of the YAP Inhibitor Verteporfin: Synthesis of Hexasubstituted Dipyrrins as Potential Inhibitors of YAP/TAZ, the Downstream Effectors of the Hippo Pathway

Cited by 65 publications

References 33 publications

Sphingosine Kinase 1/S1P Signaling Contributes to Pulmonary Fibrosis by Activating Hippo/YAP Pathway and Mitochondrial Reactive Oxygen Species in Lung Fibroblasts

Sphingosine Kinase 1/S1P Signaling Contributes to Pulmonary Fibrosis by Activating Hippo/YAP Pathway and Mitochondrial Reactive Oxygen Species in Lung Fibroblasts

A time for YAP1: Tumorigenesis, immunosuppression and targeted therapy

YAP/TAZ Activation as a Target for Treating Metastatic Cancer

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