Tricyclic Benzo[cd]azulenes Selectively Inhibit Activities of Pim Kinases and Restrict Growth of Epstein-Barr Virus-Transformed Cells

Kiriazis, Alexandros; Vahakoski, Riitta L.; Santio, Niina M.; Arnaudova, R; Eerola, Sini K.; Rainio, Eeva-Marja; Aumüller, Ingo B.; Yli‐Kauhaluoma, Jari; Koskinen, Päivi J.

doi:10.1371/journal.pone.0055409

Cited by 21 publications

(26 citation statements)

References 37 publications

(68 reference statements)

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“…GST-tagged fusion proteins were separated from glutathione sepharose beads by 30 mM glutathione in 75 mM Tris-HCl (pH 8.0), thereafter GST-tagged Pim and Notch family members were subjected to similar in vitro kinase reactions as previously described [53]. Following kinase assays, mouse N1ICD was subjected to in-gel trypsin digestion and TiO 2 affinity chromatography as previously described [54].…”

Section: Methodsmentioning

confidence: 99%

Phosphorylation of Notch1 by Pim kinases promotes oncogenic signaling in breast and prostate cancer cells

et al. 2016

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Tumorigenesis is a multistep process involving co-operation between several deregulated oncoproteins. In this study, we unravel previously unrecognized interactions and crosstalk between Pim kinases and the Notch signaling pathway, with implications for both breast and prostate cancer. We identify Notch1 and Notch3, but not Notch2, as novel Pim substrates and demonstrate that for Notch1, the serine residue 2152 is phosphorylated by all three Pim family kinases. This target site is located in the second nuclear localization sequence (NLS) of the Notch1 intracellular domain (N1ICD), and is shown to be important for both nuclear localization and transcriptional activity of N1ICD. Phosphorylation-dependent stimulation of Notch1 signaling promotes migration of prostate cancer cells, balances glucose metabolism in breast cancer cells, and supports in vivo growth of both types of cancer cells on chick embryo chorioallantoic membranes. Furthermore, Pim-induced growth of orthotopic prostate xenografts in mice is associated with enhanced nuclear Notch1 activity. Finally, simultaneous inhibition of Pim and Notch abrogates the cellular responses more efficiently than individual treatments, opening up new vistas for combinatorial cancer therapy.

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Section: Methodsmentioning

confidence: 99%

Phosphorylation of Notch1 by Pim kinases promotes oncogenic signaling in breast and prostate cancer cells

et al. 2016

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“…Celastrol, a TAK1/ NF-κB inhibitor, has also presented as a potential therapeutic molecule to ameliorate vGPCR/KSHV-induced tumors (Bottero et al, 2011). As an inhibitor of Pim kinases, the chemical compound tricyclic benzo and its derivative were shown to dramatically reduce the motility and proliferation of EBV transformed lymphoblastoid cells (Kiriazis et al, 2013). Similar effect was also observed on KSHV-induced lymphoma cells (Sarek et al, 2013).…”

Section: Future Perspectivesmentioning

confidence: 83%

The regulatory role of protein phosphorylation in human gammaherpesvirus associated cancers

et al. 2017

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Activation of specific sets of protein kinases by intracellular signal molecules has become more and more apparent in the past decade. Phosphorylation, one of key posttranslational modification events, is activated by kinase or regulatory protein and is vital for controlling many physiological functions of eukaryotic cells such as cell proliferation, differentiation, malignant transformation, and signal transduction mediated by external stimuli. Moreovers, the reversible modification of phosphorylation and dephosphorylation can result in different features of the target substrate molecules including DNA binding, protein-protein interaction, subcellular location and enzymatic activity, and is often hijacked by viral infection. Epstein-Barr virus (EBV) and Kaposi's sarcomaassociated herpesvirus (KSHV), two human oncogenic gamma-herpesviruses, are shown to tightly associate with many malignancies. In this review, we summarize the recent progresses on understanding of molecular properties and regulatory modes of cellular and viral proteins phosphorylation influenced by these two tumor viruses, and highlight the potential therapeutic targets and strategies against their related cancers.

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“…Therefore, the Pim kinases family presents a target for pharmacological inhibition in cancer therapy, in which new small molecule inhibitors are being developed, such as the BZL . Besides prostate cancer, BZL has also showed an in vitro inhibitory effect on other cancer cell lines, including breast cancer . The BZL‐loaded LNPs (BZL@LNPs) were prepared using the same solvent exchange method, and subsequently functionalized with iRGD and DSS to yield BZL@LNPs‐iRGD and BZL@LNPs‐DSS, respectively.…”

Section: Resultsmentioning

confidence: 99%

“…Therefore, BZL‐loaded LNPs and the free BZL were used to treat the cells and evaluate the growth inhibition effect of the BZL in 2D ( Figure ) and 3D ( Figure ) cell culturing models. Apart from its known role as an inhibitor of Pim kinases overexpressed in prostate cancer, BZL has been shown to be a potent cytotoxic compound against other cell lines . Thus, pure BZL and BZL‐loaded LNPs were incubated with PC3‐MM2, MDA‐MB‐231 and A549, representing the prostate, breast and lung cancers, respectively.…”

Section: Resultsmentioning

confidence: 99%

Preparation and Characterization of Dentin Phosphophoryn‐Derived Peptide‐Functionalized Lignin Nanoparticles for Enhanced Cellular Uptake

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Lintinen

et al. 2019

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The surface modification of nanoparticles (NPs) using different ligands is a common strategy to increase NP−cell interactions. Here, dentin phosphophoryn‐derived peptide (DSS) lignin nanoparticles (LNPs) are prepared and characterized, the cellular internalization of the DSS‐functionalized LNPs (LNPs‐DSS) into three different cancer cell lines is evaluated, and their efficacy with the widely used iRGD peptide is compared. It is shown that controlled extent of carboxylation of lignin improves the stability at physiological conditions of LNPs formed upon solvent exchange. Functionalization with DSS and iRGD peptides maintains the spherical morphology and moderate polydispersity of LNPs. The LNPs exhibit good cytocompatibility when cultured with PC3‐MM2, MDA‐MB‐231, and A549 in the conventional 2D model and in the 3D cell spheroid morphology. Importantly, the 3D cell models reveal augmented internalization of peptide‐functionalized LNPs and improve antiproliferative effects when the LNPs are loaded with a cytotoxic compound. Overall, LNPs‐DSS show equal or even superior cellular internalization than the LNPs‐iRGD, suggesting that DSS can also be used to enhance the cellular uptake of NPs into different types of cells, and release different cargos intracellularly.

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Tricyclic Benzo[cd]azulenes Selectively Inhibit Activities of Pim Kinases and Restrict Growth of Epstein-Barr Virus-Transformed Cells

Cited by 21 publications

References 37 publications

Phosphorylation of Notch1 by Pim kinases promotes oncogenic signaling in breast and prostate cancer cells

Phosphorylation of Notch1 by Pim kinases promotes oncogenic signaling in breast and prostate cancer cells

The regulatory role of protein phosphorylation in human gammaherpesvirus associated cancers

Preparation and Characterization of Dentin Phosphophoryn‐Derived Peptide‐Functionalized Lignin Nanoparticles for Enhanced Cellular Uptake

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