| 1. |
- Bajusz, Csaba, et al.
(author)
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The nuclear activity of the actin-binding Moesin protein is necessary for gene expression in Drosophila
- 2021
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In: The FEBS Journal. - : Wiley. - 1742-464X .- 1742-4658. ; 288:16, s. 4812-4832
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Journal article (peer-reviewed)abstract
- Ezrin-Radixin-Moesin (ERM) proteins play an essential role in the cytoplasm by cross-linking actin filaments with plasma membrane proteins. Research has identified the nuclear localization of ERMs, as well as the involvement of a single Drosophila ERM protein, Moesin, in nuclear mRNA exports. However, the question of how important the nuclear activity of ERM proteins are for the life of an organism has so far not been explored. Here, we present the first attempt to reveal the in vivo relevance of nuclear localization of Moesin in Drosophila. With the help of a nuclear export signal, we decreased the amount of Moesin in the nuclei of the animals. Furthermore, we observed various developmental defects, demonstrating the importance of ERM function in the nucleus for the first time. Transcriptome analysis of the mutant flies revealed that the lack of nuclear Moesin function leads to expression changes in nearly 700 genes, among them heat-shock genes. This result together with additional findings revealed that in Drosophila the expression of protein chaperones requires the nuclear functions of Moesin.
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| 2. |
- Berta, Judit, et al.
(author)
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Apelin promotes blood and lymph vessel formation and the growth of melanoma lung metastasis
- 2021
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1
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Journal article (peer-reviewed)abstract
- Apelin, a ligand of the APJ receptor, is overexpressed in several human cancers and plays an important role in tumor angiogenesis and growth in various experimental systems. We investigated the role of apelin signaling in the malignant behavior of cutaneous melanoma. Murine B16 and human A375 melanoma cell lines were stably transfected with apelin encoding or control vectors. Apelin overexpression significantly increased melanoma cell migration and invasion in vitro, but it had no impact on its proliferation. In our in vivo experiments, apelin significantly increased the number and size of lung metastases of murine melanoma cells. Melanoma cell proliferation rates and lymph and blood microvessel densities were significantly higher in the apelin-overexpressing pulmonary metastases. APJ inhibition by the competitive APJ antagonist MM54 significantly attenuated the in vivo pro-tumorigenic effects of apelin. Additionally, we detected significantly elevated circulating apelin and VEGF levels in patients with melanoma compared to healthy controls. Our results show that apelin promotes blood and lymphatic vascularization and the growth of pulmonary metastases of skin melanoma. Further studies are warranted to validate apelin signaling as a new potential therapeutic target in this malignancy.
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| 3. |
- Imrefi, Ildikó, et al.
(author)
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Poaceascoma zborayi sp. nov. and Agrorhizomyces patris gen. et spec. nov. : Two novel dark septate endophytes colonizing wheat (Triticum aestivum) roots from a cropland in Hungary
- 2024
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In: Mycological progress. - : Springer. - 1617-416X .- 1861-8952. ; 23:1
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Journal article (peer-reviewed)abstract
- In this study, we investigated two distinct new phylogenetic lineages of root-colonizing dark septate endophytic fungi colonizing wheat (Triticum aestivum) roots from a long-term agricultural experimental site in Hungary. According to four-locus (internal transcribed spacer, partial large and small subunit regions of nuclear ribosomal DNA, and partial translation elongation factor 1-alpha) phylogenetic analyses, the isolates belong to the Lentitheciaceae and Didymosphaeriaceae of the Pleosporales (Dothideomycetes). We studied the morphology and culture characteristics of the strains. We carried out in vitro resynthesis pot experiments with their original hosts and found no overall negative effect of the inoculation with different isolates of the new taxa. One of the lineages belonged to the genus Poaceascoma (Lentitheciaceae) and represented a novel species described here as Poaceascoma zborayi. We could describe conidia-like structures from this species. Isolates of the other lineage represented a monotypic novel genus in the Didymosphaeriaceae. Accordingly, the new genus, Agrorhizomyces, represented by the species A. patris, is introduced. Sterile, globose structures resembling immature sporocarps were detected. Sequence similarity searches indicated that P. zborayi might be widely distributed, while no sequence similar to A. patris was found outside the sampling area.
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| 4. |
- Megyesfalvi, Zsolt, et al.
(author)
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Unfolding the secrets of small cell lung cancer progression : Novel approaches and insights through rapid autopsies
- 2023
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In: Cancer Cell. - 1535-6108. ; 41:9, s. 1535-1540
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Journal article (peer-reviewed)abstract
- The understanding of small cell lung cancer (SCLC) biology has increased dramatically in recent years, but the processes that allow SCLC to progress rapidly remain poorly understood. Here, we advocate the integration of rapid autopsies and preclinical models into SCLC research as a comprehensive strategy with the potential to revolutionize current treatment paradigms.
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| 5. |
- Solta, Anna, et al.
(author)
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Entinostat Enhances the Efficacy of Chemotherapy in Small Cell Lung Cancer Through S-phase Arrest and Decreased Base Excision Repair
- 2023
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In: Clinical cancer research : an official journal of the American Association for Cancer Research. - 1078-0432. ; 29:22, s. 4644-4659
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Journal article (peer-reviewed)abstract
- PURPOSE: Acquired chemoresistance is a frequent event in small cell lung cancer (SCLC), one of the deadliest human malignancies. Histone deacetylase inhibitors (HDACi) have been shown to synergize with different chemotherapeutic agents including cisplatin. Accordingly, we aimed to investigate the dual targeting of HDAC inhibition and chemotherapy in SCLC.EXPERIMENTAL DESIGN: The efficacy of HDACi and chemotherapy in SCLC was investigated both in vitro and in vivo. Synergistic drug interactions were calculated based on the HSA model (Combenefit software). Results from the proteomic analysis were confirmed via ICP-MS, cell-cycle analysis, and comet assays.RESULTS: Single entinostat- or chemotherapy significantly reduced cell viability in human neuroendocrine SCLC cells. The combination of entinostat with either cisplatin, carboplatin, irinotecan, epirubicin, or etoposide led to strong synergy in a subset of resistant SCLC cells. Combination treatment with entinostat and cisplatin significantly decreased tumor growth in vivo. Proteomic analysis comparing the groups of SCLC cell lines with synergistic and additive response patterns indicated alterations in cell-cycle regulation and DNA damage repair. Cell-cycle analysis revealed that cells exhibiting synergistic drug responses displayed a shift from G1 to S-phase compared with cells showing additive features upon dual treatment. Comet assays demonstrated more DNA damage and decreased base excision repair in SCLC cells more responsive to combination therapy.CONCLUSIONS: In this study, we decipher the molecular processes behind synergistic interactions between chemotherapy and HDAC inhibition. Moreover, we report novel mechanisms to overcome drug resistance in SCLC, which may be relevant to increasing therapeutic success.
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| 6. |
- Torok, Szilvia, et al.
(author)
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Limited tumor tissue drug penetration contributes to primary resistance against angiogenesis inhibitors
- 2017
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In: Theranostics. - : Ivyspring International Publisher. - 1838-7640. ; 7:2, s. 400-412
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Journal article (peer-reviewed)abstract
- Resistance mechanisms against antiangiogenic drugs are unclear. Here, we correlated the antitumor and antivascular properties of five different antiangiogenic receptor tyrosine kinase inhibitors (RTKIs) (motesanib, pazopanib, sorafenib, sunitinib, vatalanib) with their intratumoral distribution data obtained by matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI). In the first mouse model, only sunitinib exhibited broad-spectrum antivascular and antitumor activities by simultaneously suppressing vascular endothelial growth factor receptor-2 (VEGFR2) and desmin expression, and by increasing intratumoral hypoxia and inhibiting both tumor growth and vascularisation significantly. Importantly, the highest and most homogeneous intratumoral drug concentrations have been found in sunitinib-treated animals. In another animal model, where - in contrast to the first model - vatalanib was detectable at homogeneously high intratumoral concentrations, the drug significantly reduced tumor growth and angiogenesis. In conclusion, the tumor tissue penetration and thus the antiangiogenic and antitumor potential of antiangiogenic RTKIs vary among the tumor models and our study demonstrates the potential of MALDI-MSI to predict the efficacy of unlabelled small molecule antiangiogenic drugs in malignant tissue. Our approach is thus a major technical and preclinical advance demonstrating that primary resistance to angiogenesis inhibitors involves limited tumor tissue drug penetration. We also conclude that MALDI-MSI may significantly contribute to the improvement of antivascular cancer therapies.
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| 7. |
- Valko, Zsuzsanna, et al.
(author)
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Dual targeting of BCL-2 and MCL-1 in the presence of BAX breaks venetoclax resistance in human small cell lung cancer
- 2023
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In: British Journal of Cancer. - : Springer Science and Business Media LLC. - 0007-0920 .- 1532-1827. ; 128:10, s. 1850-1861
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Journal article (peer-reviewed)abstract
- Background: No targeted drugs are currently available against small cell lung cancer (SCLC). BCL-2 family members are involved in apoptosis regulation and represent therapeutic targets in many malignancies. Methods: Expression of BCL-2 family members in 27 SCLC cell lines representing all known four SCLC molecular subtypes was assessed by qPCR, Western blot and mass spectrometry-based proteomics. BCL-2 and MCL-1 inhibition (venetoclax and S63845, respectively) was assessed by MTT assay and flow cytometry and in mice bearing human SCLC tumours. Drug interactions were calculated using the Combenefit software. Ectopic BAX overexpression was achieved by expression plasmids. Results: The highest BCL-2 expression levels were detected in ASCL1- and POU2F3-driven SCLC cells. Although sensitivity to venetoclax was reflected by BCL-2 levels, not all cell lines responded consistently despite their high BCL-2 expression. MCL-1 overexpression and low BAX levels were both characteristic for venetoclax resistance in SCLC, whereas the expression of other BCL-2 family members did not affect therapeutic efficacy. Combination of venetoclax and S63845 resulted in significant, synergistic in vitro and in vivo anti-tumour activity and apoptosis induction in double-resistant cells; however, this was seen only in a subset with detectable BAX. In non-responding cells, ectopic BAX overexpression sensitised to venetoclax and S63845 and, furthermore, induced synergistic drug interaction. Conclusions: The current study reveals the subtype specificity of BCL-2 expression and sheds light on the mechanism of venetoclax resistance in SCLC. Additionally, we provide preclinical evidence that combined BCL-2 and MCL-1 targeting is an effective approach to overcome venetoclax resistance in high BCL-2-expressing SCLCs with intact BAX.
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