Desmosomes are intercellular junctions that confer strong cell-cell adhesion, thus conferring resistance against mechanical stress on epithelial tissues. A body of evidence indicates that decreased expression of desmosomal proteins is associated with poor prognosis in various cancers. As a key component of desmosomal plaque proteins, the functional role of desmoplakin (DSP) in cancer is not yet elucidated. Here, we reported the anti-tumorigenic activity of DSP in non-small cell lung cancer (NSCLC). We found by DSP DNA methylation that DSP expression was downregulated in 8 out of 11 lung cancer cell lines and in 34 out of 56 primary lung tumors . Ectopic expression of DSP in the NSCLC cell line H157 significantly inhibited cell proliferation, anchorage-independent growth, migration and invasion and also increased the sensitivity of NSCLC cells to apoptosis induced by an anticancer drug, gemcitabine. Furthermore, overexpression of DSP enhanced expression of plakoglobin (γ-catenin), resulting in decreased T-cell factor/lymphoid enhancer factor (TCF/LEF)-dependent transcriptional activity and reduced expression of the Wnt/β-catenin target genes Axin2 and matrix metalloproteinase MMP14. In accordance, DSP suppression by small interfering RNA resulted in downregulation of plakoglobin and upregulation of β-catenin and MMP14. Taken together, these data suggest that DSP is inactivated in lung cancer by an epigenetic mechanism, increases the sensitivity to anticancer drug-induced apoptosis and has tumor-suppressive function, possibly through inhibition of the Wnt/β-catenin signaling pathway in NSCLC cells. The epigenetic regulation of DSP and its ability to increase the sensitivity to anticancer drug-induced apoptosis has potential implications for clinical application.

Background: Biological activities of nontoxic A␤42 peptides remain unclear in Alzheimer disease. Results: A␤ species are taken up in the nucleus of cells by a nonregulated mechanism, but only A␤42 plays a role in gene transcription. Conclusion: A␤42 may act as a transcriptional regulator, similar to the cytoplasmic fragment AICD. Significance: Genes regulated by nuclear A␤42 could represent alternative targets for therapeutic approaches.

The Fra3B locus on chromosome 3p14.2 targeting the fragile histidine triad (Fhit) gene represents one of the most common fragile sites of the human genome and is associated with early preneoplastic and malignant disorders in multiple human tumors. Fhit was classified as a tumor suppressor; however, the molecular mechanisms of its function are not well established. Here, we report that Fhit associates with the lymphoid enhancer-binding factor 1/T cell factor/␤-catenin complex by directly binding to ␤-catenin, a major player in the canonical Wnt pathway that is deregulated in numerous forms of human cancer. In binding to the ␤-catenin C-terminal domain, Fhit represses transcription of target genes such as cyclin D1, axin2, MMP-14, and survivin. Knockdown of Fhit reversed this effect, whereas this reversal was not detectable when ␤-catenin was knocked down simultaneously. The Fhit enzymatic activity as a diadenosine-polyphosphate hydrolase is not required for the down-regulation of ␤-catenin-mediated transcription as examined with an enzymatic inactive Fhit-H96N protein. ChIPs revealed recruitment of Fhit/␤-catenin complexes to target gene promoters. In soft agar assays Fhit and ␤-catenin are involved in regulation of anchorage-independent growth. These observations assign to the tumor suppressor Fhit an unexpected role in the regulation of ␤-catenin-mediated gene transcription.histidine triad ͉ T cell factor ͉ lymphoid enhancer-binding factor 1

Aberrant activation of the canonical Wnt/β-catenin signaling pathway has been reported for numerous tumors of different origins. In most cases, mutations in components of the Wnt signaling pathway or in β-catenin itself were detected which ultimately induce a genetic program that promotes cell proliferation and attenuates apoptosis. Thus, targeting of Wnt/β-catenin signaling is of specific therapeutic interest. Herein, we investigated the plant-derived isoquinoline alkaloid berberine, which has been reported to have anticancer activity, and synthetic 13-arylalkyl derivatives thereof for their effects on Wnt/β-catenin signaling. Berberine did not show major effects on viability of HEK-293 embryonic kidney and HCT116 colon carcinoma cells and was not toxic in concentrations up to 20 µM. Berberine inhibited β-catenin transcriptional activity and attenuated anchorage-independent growth. As a result of berberine treatment, cellular levels of active β-catenin were reduced concomitant with an increase in the expression of E-cadherin. However, in unstimulated cells, the effects on β-catenin levels were low. A screen of synthetic 13-arylalkyl berberine derivatives identified compounds exhibiting activities superior to those of the naturally occurring parent substance with more than 100-fold lower EC50 values for Wnt-repression. Thus, berberine and its synthetic derivatives represent potential therapeutic agents to inhibit Wnt/β-catenin signaling in tumorigenesis.

The enzymes 5-lipoxygenase (5-LO) and glycogen synthase kinase (GSK)-3 represent promising drug targets in inflammation. We made use of the bisindole core of indirubin, present in GSK-3 inhibitors, to innovatively target 5-LO at the ATP-binding site for the design of dual 5-LO/GSK-3 inhibitors. Evaluation of substituted indirubin derivatives led to the identification of (3Z)-6-bromo-3-[(3E)-3-hydroxyiminoindolin-2-ylidene]indolin-2-one (15) as a potent, direct, and reversible 5-LO inhibitor (IC50 = 1.5 μM), with comparable cellular effectiveness on 5-LO and GSK-3. Together, we present indirubins as novel chemotypes for the development of 5-LO inhibitors, the interference with the ATP-binding site as a novel strategy for 5-LO targeting, and dual 5-LO/GSK-3 inhibition as an unconventional and promising concept for anti-inflammatory intervention.

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The therapeutic activities of natural plant extracts have been well known for centuries. Many of them, in addition to antiviral and antibiotic effects, turned out to have anti-tumor activities by targeting different signaling pathways. The canonical Wnt pathway represents a major tumorigenic pathway deregulated in numerous tumor entities, including colon cancer. Here, we investigated the acylphloroglucinols hyperforin (HF) from St. John’s wort (Hypericum perforatum L.) and myrtucommulone A (MC A) from myrtle (Myrtus communis) and semi-synthetic derivatives thereof (HM 177, HM 297, HM298) for their effects on Wnt/β-catenin signaling. None of these substances revealed major cytotoxicity on STF293 embryonic kidney and HCT116 colon carcinoma cells at concentrations up to 10 μM. At this concentration, HF and HM 177 showed the strongest effect on cell proliferation, whereas MC A and HM 177 most prominently inhibited anchorage-independent growth of HCT116 cells. Western blot analyses of active β-catenin and β-catenin/TCF reporter gene assays in STF293 cells revealed inhibitory activities of HF, MC A and HM 177. In line with this, the expression of endogenous Wnt target genes, Axin and Sp5, in HCT116 cells was significantly reduced. Our data suggest that the acylphloroglucinols hyperforin, myrtucommulone A and its derivative HM 177 represent potential new therapeutic agents to inhibit Wnt/β-catenin signaling in colon cancer.

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