2021
Mickova, Alena; Kharaishvili, Gvantsa; Kurfurstova, Daniela; Gachechiladze, Mariam; Kral, Milan; Vacek, Ondrej; Pokryvkova, Barbora; Mistrik, Martin; Soucek, Karel; Bouchal, Jan
Skp2 and Slug Are Coexpressed in Aggressive Prostate Cancer and Inhibited by Neddylation Blockade. Journal Article
In: International journal of molecular sciences, vol. 22, no. 6, 2021, ISSN: 1422-0067, (Place: Switzerland).
Abstract | Links | BibTeX | Tags: *Protein Processing, Androgen/genetics/metabolism, Antigens, Antineoplastic Agents/pharmacology, Cadherins/genetics/metabolism, CD/genetics/metabolism, Cell Line, Cell Survival/drug effects, Cyclin-Dependent Kinase Inhibitor p27/genetics/metabolism, Cyclopentanes/pharmacology, Docetaxel/pharmacology, Epithelial-Mesenchymal Transition/genetics, Gene Expression Regulation, Humans, Immunohistochemistry, Lymphatic Metastasis, Male, multiplex, NEDD8 Protein/*genetics/metabolism, neddylation, Neoplasm Grading, Neoplastic, PC-3 Cells, Post-Translational, Prostate cancer, Prostate/metabolism/pathology, Prostatic Neoplasms/*genetics/metabolism/pathology, Pyrimidines/pharmacology, Receptors, RNA, S-Phase Kinase-Associated Proteins/antagonists & inhibitors/*genetics/metabolism, Skp2 (S-phase kinase-associated protein 2), Slug, Small Interfering/genetics/metabolism, Snail Family Transcription Factors/*genetics/metabolism, Tumor
@article{mickova_skp2_2021,
title = {Skp2 and Slug Are Coexpressed in Aggressive Prostate Cancer and Inhibited by Neddylation Blockade.},
author = {Alena Mickova and Gvantsa Kharaishvili and Daniela Kurfurstova and Mariam Gachechiladze and Milan Kral and Ondrej Vacek and Barbora Pokryvkova and Martin Mistrik and Karel Soucek and Jan Bouchal},
doi = {10.3390/ijms22062844},
issn = {1422-0067},
year = {2021},
date = {2021-03-01},
journal = {International journal of molecular sciences},
volume = {22},
number = {6},
abstract = {Prostate cancer (PCa) is the second leading cause of cancer-related deaths in men in Western countries, and there is still an urgent need for a better understanding of PCa progression to inspire new treatment strategies. Skp2 is a substrate-recruiting component of the E3 ubiquitin ligase complex, whose activity is regulated through neddylation. Slug is a transcriptional repressor involved in the epithelial-to-mesenchymal transition, which may contribute to therapy resistance. Although Skp2 has previously been associated with a mesenchymal phenotype and prostate cancer progression, the relationship with Slug deserves further elucidation. We have previously shown that a high Gleason score (≥8) is associated with higher Skp2 and lower E-cadherin expression. In this study, significantly increased expression of Skp2, AR, and Slug, along with E-cadherin downregulation, was observed in primary prostate cancer in patients who already had lymph node metastases. Skp2 was slightly correlated with Slug and AR in the whole cohort (Rs 0.32 and 0.37, respectively), which was enhanced for both proteins in patients with high Gleason scores (Rs 0.56 and 0.53, respectively) and, in the case of Slug, also in patients with metastasis to lymph nodes (Rs 0.56). Coexpression of Skp2 and Slug was confirmed in prostate cancer tissues by multiplex immunohistochemistry and confocal microscopy. The same relationship between these two proteins was observed in three sets of prostate epithelial cell lines (PC3, DU145, and E2) and their mesenchymal counterparts. Chemical inhibition of Skp2, but not RNA interference, modestly decreased Slug protein in PC3 and its docetaxel-resistant subline PC3 DR12. Importantly, chemical inhibition of Skp2 by MLN4924 upregulated p27 and decreased Slug expression in PC3, PC3 DR12, and LAPC4 cells. Novel treatment strategies targeting Skp2 and Slug by the neddylation blockade may be promising in advanced prostate cancer, as recently documented for other aggressive solid tumors.},
note = {Place: Switzerland},
keywords = {*Protein Processing, Androgen/genetics/metabolism, Antigens, Antineoplastic Agents/pharmacology, Cadherins/genetics/metabolism, CD/genetics/metabolism, Cell Line, Cell Survival/drug effects, Cyclin-Dependent Kinase Inhibitor p27/genetics/metabolism, Cyclopentanes/pharmacology, Docetaxel/pharmacology, Epithelial-Mesenchymal Transition/genetics, Gene Expression Regulation, Humans, Immunohistochemistry, Lymphatic Metastasis, Male, multiplex, NEDD8 Protein/*genetics/metabolism, neddylation, Neoplasm Grading, Neoplastic, PC-3 Cells, Post-Translational, Prostate cancer, Prostate/metabolism/pathology, Prostatic Neoplasms/*genetics/metabolism/pathology, Pyrimidines/pharmacology, Receptors, RNA, S-Phase Kinase-Associated Proteins/antagonists & inhibitors/*genetics/metabolism, Skp2 (S-phase kinase-associated protein 2), Slug, Small Interfering/genetics/metabolism, Snail Family Transcription Factors/*genetics/metabolism, Tumor},
pubstate = {published},
tppubtype = {article}
}
Prostate cancer (PCa) is the second leading cause of cancer-related deaths in men in Western countries, and there is still an urgent need for a better understanding of PCa progression to inspire new treatment strategies. Skp2 is a substrate-recruiting component of the E3 ubiquitin ligase complex, whose activity is regulated through neddylation. Slug is a transcriptional repressor involved in the epithelial-to-mesenchymal transition, which may contribute to therapy resistance. Although Skp2 has previously been associated with a mesenchymal phenotype and prostate cancer progression, the relationship with Slug deserves further elucidation. We have previously shown that a high Gleason score (≥8) is associated with higher Skp2 and lower E-cadherin expression. In this study, significantly increased expression of Skp2, AR, and Slug, along with E-cadherin downregulation, was observed in primary prostate cancer in patients who already had lymph node metastases. Skp2 was slightly correlated with Slug and AR in the whole cohort (Rs 0.32 and 0.37, respectively), which was enhanced for both proteins in patients with high Gleason scores (Rs 0.56 and 0.53, respectively) and, in the case of Slug, also in patients with metastasis to lymph nodes (Rs 0.56). Coexpression of Skp2 and Slug was confirmed in prostate cancer tissues by multiplex immunohistochemistry and confocal microscopy. The same relationship between these two proteins was observed in three sets of prostate epithelial cell lines (PC3, DU145, and E2) and their mesenchymal counterparts. Chemical inhibition of Skp2, but not RNA interference, modestly decreased Slug protein in PC3 and its docetaxel-resistant subline PC3 DR12. Importantly, chemical inhibition of Skp2 by MLN4924 upregulated p27 and decreased Slug expression in PC3, PC3 DR12, and LAPC4 cells. Novel treatment strategies targeting Skp2 and Slug by the neddylation blockade may be promising in advanced prostate cancer, as recently documented for other aggressive solid tumors.
2007
Zatloukalová, Jirina; Svihálková-Sindlerová, Lenka; Kozubík, Alois; Krcmár, Pavel; Machala, Miroslav; Vondrácek, Jan
In: Biochemical pharmacology, vol. 73, no. 10, pp. 1622–1634, 2007, ISSN: 0006-2952, (Place: England).
Abstract | Links | BibTeX | Tags: Animals, Aryl Hydrocarbon/genetics/*metabolism, beta-Naphthoflavone/*pharmacology, Cadherins/genetics/metabolism, Cell Proliferation/*drug effects, Cells, Cultured, Cytochrome P-450 CYP1A1/genetics/metabolism, Flavonoids/*pharmacology, Gene Expression/*drug effects/physiology, Hepatocytes/*drug effects/physiology, Inbred F344, Liver/cytology, NAD(P)H Dehydrogenase (Quinone)/genetics/metabolism, Rats, Receptors
@article{zatloukalova_beta-naphthoflavone_2007,
title = {beta-Naphthoflavone and 3'-methoxy-4'-nitroflavone exert ambiguous effects on Ah receptor-dependent cell proliferation and gene expression in rat liver 'stem-like' cells.},
author = {Jirina Zatloukalová and Lenka Svihálková-Sindlerová and Alois Kozubík and Pavel Krcmár and Miroslav Machala and Jan Vondrácek},
doi = {10.1016/j.bcp.2007.01.032},
issn = {0006-2952},
year = {2007},
date = {2007-05-01},
journal = {Biochemical pharmacology},
volume = {73},
number = {10},
pages = {1622–1634},
abstract = {Both natural and synthetic flavonoids are known to interact with the aryl hydrocarbon receptor (AhR); however, their agonist/antagonist properties in vitro have been so far studied mostly in the context of cytochrome P450 1A1 gene (Cyp1a1) regulation. We investigated effects of two synthetic flavones known either as AhR agonist (beta-naphthoflavone; BNF) or antagonist (3'-methoxy-4'-nitroflavone; 3M4NF), using an in vitro model of liver 'stem-like' cells, on expression of various AhR target genes and AhR-dependent cell proliferation. We found that the presumed antagonist 3M4NF induces a partial nuclear translocation and activation of AhR. Although inhibiting the 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced Cyp1a1 expression, 3M4NF alone induced a minor increase of CYP1A1 mRNA and protein. However, 3M4NF did not induce AhR binding to synthetic dioxin response elements (DRE). In contrast to Cyp1a1, 3M4NF induced a marked expression of other AhR-regulated genes, such as Cyp1b1 and Nqo1, as well as transcriptional repression of Cdh13 gene, confirming that its effects may be promoter-context specific. Like BNF, 3M4NF induced AhR-dependent cell proliferation of contact-inhibited rat liver 'stem-like' WB-F344 cells, associated with a marked upregulation of Cyclin A, as well as the downregulation of proteins involved in formation of cell-cell contacts. Based on these experimental findings, we conclude that partial agonists/antagonists of AhR can increase cell proliferation rate and AhR-dependent genes expression in both cell type- and gene-specific manner. The specificity of effects of flavones on diverse AhR targets should be taken into account, when studying AhR signaling using presumed AhR antagonists.},
note = {Place: England},
keywords = {Animals, Aryl Hydrocarbon/genetics/*metabolism, beta-Naphthoflavone/*pharmacology, Cadherins/genetics/metabolism, Cell Proliferation/*drug effects, Cells, Cultured, Cytochrome P-450 CYP1A1/genetics/metabolism, Flavonoids/*pharmacology, Gene Expression/*drug effects/physiology, Hepatocytes/*drug effects/physiology, Inbred F344, Liver/cytology, NAD(P)H Dehydrogenase (Quinone)/genetics/metabolism, Rats, Receptors},
pubstate = {published},
tppubtype = {article}
}
Both natural and synthetic flavonoids are known to interact with the aryl hydrocarbon receptor (AhR); however, their agonist/antagonist properties in vitro have been so far studied mostly in the context of cytochrome P450 1A1 gene (Cyp1a1) regulation. We investigated effects of two synthetic flavones known either as AhR agonist (beta-naphthoflavone; BNF) or antagonist (3'-methoxy-4'-nitroflavone; 3M4NF), using an in vitro model of liver 'stem-like' cells, on expression of various AhR target genes and AhR-dependent cell proliferation. We found that the presumed antagonist 3M4NF induces a partial nuclear translocation and activation of AhR. Although inhibiting the 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced Cyp1a1 expression, 3M4NF alone induced a minor increase of CYP1A1 mRNA and protein. However, 3M4NF did not induce AhR binding to synthetic dioxin response elements (DRE). In contrast to Cyp1a1, 3M4NF induced a marked expression of other AhR-regulated genes, such as Cyp1b1 and Nqo1, as well as transcriptional repression of Cdh13 gene, confirming that its effects may be promoter-context specific. Like BNF, 3M4NF induced AhR-dependent cell proliferation of contact-inhibited rat liver 'stem-like' WB-F344 cells, associated with a marked upregulation of Cyclin A, as well as the downregulation of proteins involved in formation of cell-cell contacts. Based on these experimental findings, we conclude that partial agonists/antagonists of AhR can increase cell proliferation rate and AhR-dependent genes expression in both cell type- and gene-specific manner. The specificity of effects of flavones on diverse AhR targets should be taken into account, when studying AhR signaling using presumed AhR antagonists.