Pentachloropseudilin Inhibits Transforming Growth Factor‐β (TGF‐β) Activity by Accelerating Cell‐Surface Type II TGF‐β Receptor Turnover in Target Cells

Chung, Chaeuk; Wang, Shih-Wei; Martin, René; Knölker, Hans‐Joachim; Kao, Yu Chen; Lin, Ming‐Hong; Chen, Jih Jung; Huang, Yaw‐Bin; Wu, Deng‐Chyang; Chen, Chunlin

doi:10.1002/cbic.201700693

Cited by 16 publications

(18 citation statements)

References 43 publications

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“…Notably, several studies suggested PAI-1 acted as an important factor involved in tumor metastasis. PAI-1 had been regarded as a mesenchymal marker and thoroughly confirmed to be a pivotal downstream effector on EMT induced by TGF-β in various cancer, such as lung cancer, gastric cancer and colorectal carcinoma cells [41][42][43][44]. It was also observed that PAI-1/PIAS3/Stat3/miR-34a feedback loop enhanced EMT-mediated metastasis through Stat3 signaling in non-small cell lung cancer (NSCLC) [45].…”

Section: Discussionmentioning

confidence: 99%

Tumor-secreted PAI-1 promotes breast cancer metastasis via the induction of adipocyte-derived collagen remodeling

Wei

et al. 2019

Cell Commun Signal

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Background: Breast cancer cells recruit surrounding stromal cells, such as cancer-associated fibroblasts (CAFs), to remodel collagen and promote tumor metastasis. Adipocytes are the most abundant stromal partners in breast tissue, local invasion of breast cancer leads to the proximity of cancer cells and adipocytes, which respond to generate cancer-associated adipocytes (CAAs). These cells exhibit enhanced secretion of extracellular matrix related proteins, including collagens. However, the role of adipocyte-derived collagen on breast cancer progression still remains unclear. Methods: Adipocytes were cocultured with breast cancer cells for 3D collagen invasion and collagen organization exploration. Breast cancer cells and adipose tissue co-implanted mouse model, clinical breast cancer samples analysis were used to study the crosstalk between adipose and breast cancer cells in vivo. A combination of proteomics, enzyme-linked immunosorbent assay, loss of function assay, qPCR, western blot, database analysis and chromatin immunoprecipitation assays were performed to study the mechanism mediated the activation of PLOD2 in adipocytes. Results: It was found that CAAs remodeled collagen alignment during crosstalk with breast cancer cells in vitro and in vivo, which further promoted breast cancer metastasis. Tumor-derived PAI-1 was required to activate the expression of the intracellular enzyme procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2) in CAAs. Pharmacologic blockade of PAI-1 or PLOD2 disrupted the collagen reorganization in CAAs. Mechanistically, it was observed that PI3K/AKT pathway was activated in adipocytes upon co-culturing with breast cancer cells or treatment with recombinant PAI-1, which could promote the translocation of transcription factor FOXP1 into the nucleus and further enhanced the promoter activity of PLOD2 in CAAs. In addition, collagen reorganization at the tumor-adipose periphery, as well as the positive relevance between PAI-1 and PLOD2 in invasive breast carcinoma were confirmed in clinical specimens of breast cancer. Conclusion: In summary, our findings revealed a new stromal collagen network that favors tumor invasion and metastasis establish between breast cancer cells and surrounding adipocytes at the tumor invasive front, and identified PLOD2 as a therapeutic target for metastatic breast cancer treatment.

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Section: Discussionmentioning

confidence: 99%

Tumor-secreted PAI-1 promotes breast cancer metastasis via the induction of adipocyte-derived collagen remodeling

Wei

et al. 2019

Cell Commun Signal

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“…Recently, we reported that among the inhibitors of nonconventional myosins, namely pentachloropseudilin (PClP) [51] and pentabromopseudilin (PBrP) [52], PClP is a reversible and allosteric inhibitor of Myo1c, which inhibits the delivery of TβRII to the plasma membrane through the lipid-raft recycling machinery, resulting in the accumulation of receptors in late endosomes and recycling compartments, and it eventually is rerouted for subsequent degradation in lysosomes. PBrP, a marine antibiotic which was initially purified from the marine bacteria Pseudomonas bromoutiliz and Alteromonas luteoviolaceus .…”

Section: Tgf-β Signaling Is Modulated By Receptor Traffickingmentioning

confidence: 99%

“…This function is supported by the finding that Myo1c facilitates the exocytosis and delivery of several raft-associated proteins, such as VEGFR2 [53], aquaporin 2 [65], GLUT4 [66], and NEPH1 [67], to the cell surface. Our recent work identified PClP as a reversible and allosteric inhibitor of Myo1c that inhibits the delivery of TβRII to the plasma membrane through the lipid-raft recycling machinery, resulting in the accumulation of receptors in late endosomes and recycling compartments, and it eventually is rerouted for subsequent degradation in lysosomes [51].…”

Section: Myosin Imentioning

confidence: 99%

Roles of Myosin-Mediated Membrane Trafficking in TGF-β Signaling

Chung

Tai

et al. 2019

IJMS

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Recent findings have revealed the role of membrane traffic in the signaling of transforming growth factor-β (TGF-β). These findings originate from the pivotal function of TGF-β in development, cell proliferation, tumor metastasis, and many other processes essential in malignancy. Actin and unconventional myosin have crucial roles in subcellular trafficking of receptors; research has also revealed a growing number of unconventional myosins that have crucial roles in TGF-β signaling. Unconventional myosins modulate the spatial organization of endocytic trafficking and tether membranes or transport them along the actin cytoskeletons. Current models do not fully explain how membrane traffic forms a bridge between TGF-β and the downstream effectors that produce its functional responsiveness, such as cell migration. In this review, we present a brief overview of the current knowledge of the TGF-β signaling pathway and the molecular components that comprise the core pathway as follows: ligands, receptors, and Smad mediators. Second, we highlight key role(s) of myosin motor-mediated protein trafficking and membrane domain segregation in the modulation of the TGF-β signaling pathway. Finally, we review future challenges and provide future prospects in this field.

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“…Several pharmacological approaches have been used to prevent TGF-β signalling, including small-molecule inhibitors, antisense oligonucleotides and monoclonal antibodies. Small-molecule inhibitors of TGF-β signalling are valuable as scientific tools for understanding TGF-β-mediated biological processes and can be utilised as leads for developing therapeutic agents to treat many severe diseases associated with TGF-β malfunction 30 .…”

Section: Discussionmentioning

confidence: 99%

Pentabromopseudilin: a myosin V inhibitor suppresses TGF-β activity by recruiting the type II TGF-β receptor to lysosomal degradation

Wang

Chung

Kao

et al. 2018

Journal of Enzyme Inhibition and Medicinal Chemistry

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Pentabromopseudilin (PBrP) is a marine antibiotic isolated from the marine bacteria Pseudomonas bromoutilis and Alteromonas luteoviolaceus. PBrP exhibits antimicrobial, anti-tumour, and phytotoxic activities. In mammalian cells, PBrP is known to act as a reversible and allosteric inhibitor of myosin Va (MyoVa). In this study, we report that PBrP is a potent inhibitor of transforming growth factor-β (TGF-β) activity. PBrP inhibits TGF-β-stimulated Smad2/3 phosphorylation, plasminogen activator inhibitor-1 (PAI-1) protein production and blocks TGF-β-induced epithelial–mesenchymal transition in epithelial cells. PBrP inhibits TGF-β signalling by reducing the cell-surface expression of type II TGF-β receptor (TβRII) and promotes receptor degradation. Gene silencing approaches suggest that MyoVa plays a crucial role in PBrP-induced TβRII turnover and the subsequent reduction of TGF-β signalling. Because, TGF-β signalling is crucial in the regulation of diverse pathophysiological processes such as tissue fibrosis and cancer development, PBrP should be further explored for its therapeutic role in treating fibrotic diseases and cancer.

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Pentachloropseudilin Inhibits Transforming Growth Factor‐β (TGF‐β) Activity by Accelerating Cell‐Surface Type II TGF‐β Receptor Turnover in Target Cells

Cited by 16 publications

References 43 publications

Tumor-secreted PAI-1 promotes breast cancer metastasis via the induction of adipocyte-derived collagen remodeling

Tumor-secreted PAI-1 promotes breast cancer metastasis via the induction of adipocyte-derived collagen remodeling

Roles of Myosin-Mediated Membrane Trafficking in TGF-β Signaling

Pentabromopseudilin: a myosin V inhibitor suppresses TGF-β activity by recruiting the type II TGF-β receptor to lysosomal degradation

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