Small molecule/ML327 mediated transcriptional de-repression of E-cadherin and inhibition of epithelial-to-mesenchymal transition

An, Hanbing; Stoops, Sydney L.; Deane, Natasha G.; Zhu, Jing; Zi, Jinghuan; Weaver, Connie; Waterson, Alex G.; Zijlstra, Andries; Lindsley, Craig W.; Beauchamp, R. Daniel

doi:10.18632/oncotarget.4473

Cited by 11 publications

(19 citation statements)

References 30 publications

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“…We have previously reported partial reversal of TGF-β-induced EMT with ML327 (10 μM) in an immortalized mouse mammary epithelial cell line [10]. This EMT reversal was associated with upregulation of E-cadherin, a hallmark of epithelial cell fate, as well as a downregulation of the mesenchymal marker, Vimentin.…”

Section: Resultsmentioning

confidence: 95%

“…ML327 was synthesized as previously described through the Vanderbilt Institute of Chemical Biology [10]. ML327 was solubilized in DMSO.…”

Section: Methodsmentioning

confidence: 99%

“…Chemical optimization of our initial “hit” yielded a chemical probe, ML327 ( N -(3-(2-hydroxynicotinamido) propyl)-5-phenylisoxazole-3-carboxamide), that partially reverses EMT in advanced epithelial cancers [9]. ML327 does not alter the cellular viability of colon and lung cancer cells, but is capable of blocking carcinoma cell invasiveness in vivo [10]. Intriguingly, we have recently reported that induction of partial mesenchymal-to-epithelial transition (MET) in neural crest-derived neuroblastomas blocks growth both in vitro and in vivo by inducing cell cycle arrest and necrosis, highlighting the therapeutic potential of this small molecule in cancers of non-epithelial origin [11].…”

Section: Introductionmentioning

confidence: 99%

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ML327 induces apoptosis and sensitizes Ewing sarcoma cells to TNF-related apoptosis-inducing ligand

Rellinger

Padmanabhan²,

Qiao

et al. 2017

Biochemical and Biophysical Research Communications

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Ewing sarcomas are rare mesenchymal-derived bone and soft tissue tumors in children. Afflicted children with distant metastases have poor survival despite aggressive therapeutics. Epithelial-to-mesenchymal transition in epithelial carcinomas is associated with loss of E-cadherin and resistance to apoptosis. ML327 is a novel small molecule that we have previously shown to reverse epithelial-to-mesenchymal transition features in both epithelial and neural crest-derived cancers. Herein, we sought to evaluate the effects of ML327 on mesenchymal-derived Ewing sarcoma cells, hypothesizing that ML327 initiates growth arrest and sensitizes to TNF-related apoptosis-inducing ligand. ML327 induced protein expression changes, increased E-cadherin and decreased vimentin, consistent with partial induction of mesenchymal-to-epithelial transition in multiple Ewing Sarcoma cell lines (SK-N-MC, TC71, and ES-5838). Induction of epithelial features was associated with apoptosis, as demonstrated by PARP and Caspase 3 cleavage by immunoblotting. Cell cycle analysis validated these findings by marked induction of the subG0 cell population. In vitro combination treatment with TRAIL demonstrated additive induction of apoptotic markers. Taken together, these findings establish a rationale for further in vivo trials of ML327 in cells of mesenchymal origin both alone and in combination with TRAIL.

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Section: Resultsmentioning

confidence: 95%

“…ML327 was synthesized as previously described through the Vanderbilt Institute of Chemical Biology [10]. ML327 was solubilized in DMSO.…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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ML327 induces apoptosis and sensitizes Ewing sarcoma cells to TNF-related apoptosis-inducing ligand

Rellinger

Padmanabhan²,

Qiao

et al. 2017

Biochemical and Biophysical Research Communications

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“…4C). E-cadherin is one of the epithelial molecular markers that is always downregulated during EMT progression [27,28].…”

Section: Effects Of Fgf18 On the Expression Of Proliferation- Migratmentioning

confidence: 99%

FGF18 Enhances Migration and the Epithelial-Mesenchymal Transition in Breast Cancer by Regulating Akt/GSK3β/Β-Catenin Signaling

Song

Zhong

et al. 2018

Cell Physiol Biochem

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Background/Aims: Fibroblast growth factors (FGFs) and their high-affinity receptors contribute to autocrine and paracrine growth stimulation in several human malignant tumors, including breast cancer. However, the mechanisms underlying the carcinogenic actions of FGF18 remain unclear. Methods: The transcription level of FGF18 under the hypoxic condition was detected with quantitative PCR (qPCR). A wound-healing assay was performed to assess the role of FGF18 in cell migration. A clonogenicity assay was used to determine whether FGF18 silencing affected cell clonogenicity. Western blotting was performed to investigate Akt/GSK3β/β-catenin pathway protein expression. Binding of β-catenin to the target gene promoter was determined by chromatin immunoprecipitation (ChIP) assays. Results: FGF18 promoted the epithelial-mesenchymal transition (EMT) and migration in breast cancer cells through activation of the Akt/GSK3β/β-catenin pathway. FGF18 increased Akt-Ser473 and -Thr308 phosphorylation, as well as that of GSK3β-Ser9. FGF18 also enhanced the transcription of proliferation-related genes (CDK2, CCND2, Ki67), metastasis-related genes (TGF-β, MMP-2, MMP-9), and EMT markers (Snail-1, Snail-2, N-cadherin, vimentin, TIMP1). β-catenin bound to the target gene promoter on the ChIP assay. Conclusion: FGF18 contributes to the migration and EMT of breast cancer cells following activation of the Akt/GSK3β/β-catenin pathway. FGF18 expression may be a potential prognostic therapeutic marker for breast cancer.

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“…We have demonstrated that this compound has a profound effect on the expression of e-cadherin at multiple timepoints at both the protein and mRNA level, and is capable of reversing the EMT phenotype and reducing the invasive potential of SW620 cell lines. 7 Compound 11r possesses an excellent in vitro DMPK profile, albeit with significant differences in data between species. Although the mouse clearance was well in excess of hepatic blood flow, low intrinsic clearance was noted in rat (33.1 mL/min/kg) and neglible instrinsic clearance was noted in human microsomal studies.…”

mentioning

confidence: 99%

Optimization of a small molecule probe that restores e-cadherin expression

Brogan

Stoops

Brady

et al. 2015

Bioorganic & Medicinal Chemistry Letters

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E-cadherin is a ubiquitous trans-membrane protein that has important functions in cellular contacts and has been shown to play a role in the epithelial mesenchymal transition. We have previously reported the use of an HTS screen to identify compounds that are capable of restoring e-cadherin in cancer cells. Here, we report the additional medicinal chemistry optimization of these molecules, resulting in new molecules that restore e-cadherin expression at low micromolar concentrations. Further, we report preliminary pharmacokinetic data on a compound, ML327, that can be used as a probe of e-cadherin restoration.

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Small molecule/ML327 mediated transcriptional de-repression of E-cadherin and inhibition of epithelial-to-mesenchymal transition

Cited by 11 publications

References 30 publications

ML327 induces apoptosis and sensitizes Ewing sarcoma cells to TNF-related apoptosis-inducing ligand

ML327 induces apoptosis and sensitizes Ewing sarcoma cells to TNF-related apoptosis-inducing ligand

FGF18 Enhances Migration and the Epithelial-Mesenchymal Transition in Breast Cancer by Regulating Akt/GSK3β/Β-Catenin Signaling

Optimization of a small molecule probe that restores e-cadherin expression

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