Wnt pathway reprogramming during human embryonal carcinoma differentiation and potential for therapeutic targeting

Snow, Grace E.; Kasper, Allison C; Busch, Alexander M.; Schwarz, Elisabeth; Ewings, Katherine; Bee, Thomas; Spinella, Michael J.; Dmitrovsky, Ethan; Freemantle, Sarah J.

doi:10.1186/1471-2407-9-383

Cited by 26 publications

(19 citation statements)

References 44 publications

(61 reference statements)

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“…Wnt10b is involved in cell growth in the presence of growth factors [33] and maintains self-renewal of stem cells [34]. Fz5 mediates cell growth of endothelial cells, possibly via its binding to Wnt10b [35], and its down-regulation in human progenitor cells (NT2/D1 cells) inhibits cell growth [36]. Therefore, we assume that the early down-regulation of Dkk1, Wnt10b and Fz5 might help to stop cell proliferation and triggers the differentiation of ReNcell VM cells.…”

Section: Two Different Regulation Waves Of Endogenous Wnt Signaling Mmentioning

confidence: 99%

Quantitative and kinetic profile of Wnt/β-catenin signaling components during human neural progenitor cell differentiation

Mazemondet¹,

Hübner

Frahm

et al. 2011

Cellular and Molecular Biology Letters

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ReNcell VM is an immortalized human neural progenitor cell line with the ability to differentiate in vitro into astrocytes and neurons, in which the Wnt/β-catenin pathway is known to be involved. However, little is known about kinetic changes of this pathway in human neural progenitor cell differentiation. In the present study, we provide a quantitative profile of Wnt/β-catenin pathway dynamics showing its spatio-temporal regulation during ReNcell VM cell differentiation. We show first that T-cell factor dependent transcription can be activated by stabilized β-catenin. Furthermore, endogenous Wnt ligands, pathway receptors and signaling molecules are temporally controlled, demonstrating changes related to differentiation stages. During the first three hours of differentiation the signaling molecules LRP6, Dvl2 and β-catenin are spatio-temporally regulated between distinct cellular compartments. From 24 h onward, components of the Wnt/β-catenin pathway are strongly activated and regulated as shown by mRNA up-regulation of Wnt ligands (Wnt5a and Wnt7a), receptors including Frizzled-2, -3, -6, -7, and -9, and co-receptors, and target genes including Axin2. This detailed temporal profile of the Wnt/β-catenin pathway is a first step to understand, control and to orientate, in vitro, human neural progenitor cell differentiation.

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Section: Two Different Regulation Waves Of Endogenous Wnt Signaling Mmentioning

confidence: 99%

Quantitative and kinetic profile of Wnt/β-catenin signaling components during human neural progenitor cell differentiation

Mazemondet¹,

Hübner

Frahm

et al. 2011

Cellular and Molecular Biology Letters

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“…A series of studies mentioned that Wnt signaling may be a potential therapeutic target for lung cancer (6)(7)(8)(9). β-catenin, a key downstream effector of the signaling pathway, mediates the canonical Wnt signals.…”

Section: Introductionmentioning

confidence: 99%

Inhibitory effects of XAV939 on the proliferation of small‑cell lung cancer H446 cells and Wnt/β‑catenin signaling pathway in�vitro

et al. 2018

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Lung cancer, including small-cell lung carcinoma (SCLC) and non-small cell lung carcinoma (NSCLC), are the most common tumor types, which represent 13% of newly diagnosed cancer cases worldwide. SCLC represents 15% of all lung cancer cases. Although an increasing number of novel targeted drugs are employed for the treatment of NSCLC, including Iressa, Tarceva and Conmana, there have been almost no major breakthroughs in SCLC over the last 30 years. Therefore, new drug targets are required to treat or prevent SCLC. Aberrant Wnt signaling is associated with numerous types of tumors, and it plays a key role in cell proliferation and survival. Recent preclinical studies suggested that XAV939 is a small-molecule inhibitor of the Wnt signaling pathway. In the present study, whether XAV939 is able to inhibit the proliferation of SCLC cells and the underlying mechanism were investigated. The inhibition of cell proliferation was detected by Cell Counting Kit-8 (CCK-8) assay. The mRNA expression of β-catenin and cyclin D1 were detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and the protein expression of β-catenin and cyclin D1 was determined by western blotting. The results from the CCK-8 cell viability assay confirmed that XAV939 is able to inhibit the proliferation of SCLC cells in a dose-dependent manner. However, the effects of XAV939 were not time-dependent. By contrast, the effect of DDP treatment was time- and dose-dependent. Furthermore, the effect of combination treatment with XAV939 and DDP was antagonistic at low doses and synergistic at high doses. It was also observed that the mRNA and protein expression of β-catenin and cyclin D1 was significantly in SCLC cells following XAV939 treatment compared with the control group. These findings suggested that XAV939 is able to inhibit the proliferation of H446 cells, at least partially, through downregulating the Wnt/β-catenin signaling pathway. All of these results may provide potential therapeutic approaches for the treatment of SCLC.

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“…38 Antibodies and dilutions were: Ptch1 1:200 (sc-6148; Santa Cruz Biotechnology), Meis1/2 1:500 (sc-10599; Santa Cruz Biotechnology), and Actin C-11 1:5000 (sc-1615; Santa Cruz Biotechnology). Speciesspecific horseradish peroxidase (HRP)-linked secondary antibodies were used with the Lumina Forte electrochemiluminescent detection reagent (EMD-Millipore).…”

Section: Immunoblot Analysismentioning

confidence: 99%

All-trans-retinoic acid antagonizes the hedgehog pathway by inducing patched

Busch¹,

Galimberti²,

Nehls³

et al. 2014

Cancer Biology & Therapy

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Male germ cell tumors (GCTs) are a model for a curable solid tumor. GCTs can differentiate into mature teratomas. Embryonal carcinomas (ECs) represent the stem cell compartment of GCTs and are the malignant counterpart to embryonic stem (ES) cells. GCTs and EC cells are useful to investigate differentiation therapy and chemotherapy response. This study explored mechanistic interactions between all-trans-retinoic acid (RA), which induces differentiation of EC and ES cells, and the Hedgehog (Hh) pathway, a regulator of self-renewal and proliferation. RA was found to induce mRNA and protein expression of Patched 1 (Ptch1), the Hh ligand receptor and negative regulator of this pathway. PTCH1 is also a target gene of Hh signaling through Smoothened (Smo) activation. Yet, this observed RA-mediated Ptch1 induction was independent of Smo. It occurred despite co-treatment with RA and Smo inhibitors. Retinoid induction of Ptch1 also occurred in other RA-responsive cancer cell lines and in normal ES cells. Notably, this enhanced Ptch1 expression was preceded by induction of the homeobox transcription factor Meis1, a direct RA target. Direct interaction between Meis1 and Ptch1 was confirmed using chromatin immunoprecipitation assays. To establish the translational relevance of this work, Ptch1 expression was shown to be deregulated in human ECs relative to mature teratoma and the normal seminiferous tubule. Taken together, these findings reveal a previously unrecognized mechanism through which RA can inhibit the Hh pathway via Ptch1 induction. Engaging this pathway is a new way to repress the Hh pathway that can be translated into the cancer clinic.

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Wnt pathway reprogramming during human embryonal carcinoma differentiation and potential for therapeutic targeting

Cited by 26 publications

References 44 publications

Quantitative and kinetic profile of Wnt/β-catenin signaling components during human neural progenitor cell differentiation

Quantitative and kinetic profile of Wnt/β-catenin signaling components during human neural progenitor cell differentiation

Inhibitory effects of XAV939 on the proliferation of small‑cell lung cancer H446 cells and Wnt/β‑catenin signaling pathway in�vitro

All-trans-retinoic acid antagonizes the hedgehog pathway by inducing patched

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