The family of PIM serine/threonine kinases includes three highly conserved oncogenes,
and
, which regulate multiple prosurvival pathways and cooperate with other oncogenes such as
. Recent genomic ...CRISPR-Cas9 screens further highlighted oncogenic functions of PIMs in diffuse large B-cell lymphoma (DLBCL) cells, justifying the development of small-molecule PIM inhibitors and therapeutic targeting of PIM kinases in lymphomas. However, detailed consequences of PIM inhibition in DLBCL remain undefined. Using chemical and genetic PIM blockade, we comprehensively characterized PIM kinase-associated prosurvival functions in DLBCL and the mechanisms of PIM inhibition-induced toxicity. Treatment of DLBCL cells with SEL24/MEN1703, a pan-PIM inhibitor in clinical development, decreased BAD phosphorylation and cap-dependent protein translation, reduced MCL1 expression, and induced apoptosis. PIM kinases were tightly coexpressed with MYC in diagnostic DLBCL biopsies, and PIM inhibition in cell lines and patient-derived primary lymphoma cells decreased MYC levels as well as expression of multiple MYC-dependent genes, including
. Chemical and genetic PIM inhibition upregulated surface CD20 levels in an MYC-dependent fashion. Consistently, MEN1703 and other clinically available pan-PIM inhibitors synergized with the anti-CD20 monoclonal antibody rituximab
, increasing complement-dependent cytotoxicity and antibody-mediated phagocytosis. Combined treatment with PIM inhibitor and rituximab suppressed tumor growth in lymphoma xenografts more efficiently than either drug alone. Taken together, these results show that targeting PIM in DLBCL exhibits pleiotropic effects that combine direct cytotoxicity with potentiated susceptibility to anti-CD20 antibodies, justifying further clinical development of such combinatorial strategies. SIGNIFICANCE: These findings demonstrate that inhibition of PIM induces DLBCL cell death via MYC-dependent and -independent mechanisms and enhances the therapeutic response to anti-CD20 antibodies by increasing CD20 expression.
The green leafhopper, Cicadella viridis lives in symbiotic association with microorganisms. The ultrastructural and molecular analyses have shown that in the body of the C. viridis two types of ...bacteriocyte endosymbionts are present. An amplification and sequencing of 16S rRNA genes revealed that large, pleomorphic bacteria display a high similarity (94–100%) to the endosymbiont ‘Candidatus Sulcia muelleri’ (phylum Bacteroidetes), whereas long, rod-shaped microorganisms are closely related to the γ-proteobacterial symbiont Sodalis (97–99% similarity). Both endosymbionts may be harbored in their own bacteriocytes as well as may co-reside in the same bacteriocytes. The ultrastructural observations have revealed that the Sodalis-like bacteria harboring the same bacteriocytes as bacterium Sulcia may invade the cells of the latter. Bacteria Sulcia and Sodalis-like endosymbionts are transovarially transmitted from one generation to the next. However, Sodalis-like endosymbionts do not invade the ovaries individually, but only inside Sulcia cells. Apart from bacteriocyte endosymbionts, in the body of C. viridis small, rod-shaped bacteria have been detected, and have been identified as being closely related to γ-proteobacterial microorganism Pectobacterium (98–99% similarity). The latter are present in the sheath cells of the bacteriomes containing bacterium Sulcia as well as in fat body cells.
•In the body of Cicadella viridis two types of bacteriocyte endosymbionts occur.•Pleomorphic bacteria are related to ‘Candidatus Sulcia muelleri’.•Rod-shaped bacteria are related to the Sodalis-like bacteria.•Endosymbionts are transovarially transmitted from one generation to the next.
Inhibition of oncogenic transcriptional programs is a promising therapeutic strategy. A substituted tricyclic benzimidazole, SEL120-34A, is a novel inhibitor of Cyclin-dependent kinase 8 (CDK8), ...which regulates transcription by associating with the Mediator complex. X-ray crystallography has shown SEL120-34A to be a type I inhibitor forming halogen bonds with the protein's hinge region and hydrophobic complementarities within its front pocket. SEL120-34A inhibits phosphorylation of STAT1 S727 and STAT5 S726 in cancer cells in vitro. Consistently, regulation of STATs- and NUP98-HOXA9- dependent transcription has been observed as a dominant mechanism of action in vivo. Treatment with the compound resulted in a differential efficacy on AML cells with elevated STAT5 S726 levels and stem cell characteristics. In contrast, resistant cells were negative for activated STAT5 and revealed lineage commitment. In vivo efficacy in xenotransplanted AML models correlated with significant repression of STAT5 S726. Favorable pharmacokinetics, confirmed safety and in vivo efficacy provide a rationale for the further clinical development of SEL120-34A as a personalized therapeutic approach in AML.
The mitogen-activated protein kinase (MAPK)-interacting kinases 1 and 2 (MNKs 1/2) and their downstream target eIF4E, play a role in oncogenic transformation, progression and metastasis. These ...results provided rationale for development of first MNKs inhibitors, currently in clinical trials for cancer treatment. Inhibitors of the MNKs/eIF4E pathway are also proposed as treatment strategy for inflammatory conditions. Here we present results of optimization of indazole-pyridinone derived MNK1/2 inhibitors among which compounds 24 and 26, selective and metabolically stable derivatives. Both compounds decreased levels of eIF4E Ser206 phosphorylation (pSer209-eIF4E) in MOLM16 cell line. When administered in mice compounds 24 and 26 significantly improved survival rates of animals in the endotoxin lethal dose challenge model, with concomitant reduction of proinflammatory cytokine levels – TNFα and IL-6 in serum. Identified MNK1/2 inhibitors represent a novel class of immunomodulatory compounds with a potential for the treatment of inflammatory diseases including sepsis.
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•A series of indazole-pyridinone derivatives as MNK1/2 inhibitors were designed.•Compounds 24 and 26 have been identified as potent, selective, and metabolically stable derivatives.•Both compounds decreased levels of pSer209-eIF4E in MOLM16 cell line.•Treatment with both compounds protected against LPS-induced septic shock in mouse model of sepsis.
Growing evidence links stress hormones with development and progression of various cancer types. The aim of this study was to assess susceptibility of cutaneous and uveal melanoma cells to adrenaline ...(AD).
The expression of β-2-adrenergic receptor in primary cutaneous (FM-55-P), primary uveal (92-1, Mel202) and metastatic cutaneous (A375) melanoma cells was estimated at mRNA, protein and cell surface levels. The impact of AD on cell proliferation and migration was also studied.
The expression of β-2-adrenergic receptor was cell line-dependent. Adrenaline treatment caused a slight stimulation of melanoma cell proliferation and activation of matrix metalloproteinases. Adrenaline-treated uveal melanoma cells showed an increased migration rate, whereas, in cutaneous melanoma cells, no changes or even lower migration speed were observed.
Melanoma cell susceptibility to AD varies depending on origin and progression stage. Metastatic cutaneous melanoma cells were found to be less responsive to AD than primary cutaneous and uveal melanoma cells.
Gene duplications restricted to single lineage combined with an asymmetric evolution of the resulting genes may play particularly important roles in this lineage's biology. We searched and identified ...asymmetrical evolution in nine gene families that duplicated exclusively in rodents and are present as single-copies in human, dog, cow, elephant, opossum, chicken, lizard, and Western clawed frog. Among those nine gene families are Fas apoptosis inhibitory molecule (Faim), implicated in apoptosis, and Sperm antigen 6 (Spag6), implicated in sperm mobility. Both genes were duplicated in or before the Muroidea ancestor. Due to the highly asymmetric evolution of the resulting paralogs, the existence of these duplications had been previously overlooked. Interestingly, Spag6, previously regarded and characterized as a single-copy ortholog of human Spag6, turns out to be a Muroidea-specific paralog. Conversely, the newly identified, highly divergent Spag6-BC061194 is in fact the parental gene. In consequence, this gene represents a rare exception from the general rule of rapid evolution of derived rather than parental genes following gene duplication. Unusual genes such as murine Spag6 may help to understand which mechanisms are responsible for this rule.
The aim of this paper was to identify endosymbiotic microorganisms living in the body cavity of a Polish population of an aphid, Adelges (Sacchiphantes) viridis, as well as to describe their ...ultrastructure and mode of transmission between generations. Molecular data (amplification and sequencing of 16S rRNA genes) indicated that endosymbionts of A. (S.) viridis are Betaproteobacteria of the species “Candidatus Vallotia virida”. Endosymbiotic bacteria are rod-shaped and localized in the cytoplasm of specific cells, termed bacteriocytes, of host insects. Endosymbionts sharing the same bacteriocytes differ in the density of their cytoplasm. There are two morphotypes of endosymbiotic bacteria: with electron-dense cytoplasm and electron-translucent cytoplasm. Since only bacteria containing electron-dense cytoplasm were observed in the binary fusion stage, differences in density of the cytoplasm are probably due to changes in the cytoskeleton of bacteria during division. Endosymbionts of A. (S.) viridis are transovarially (i.e. via oocytes) transmitted from the mother to the offspring.
•All the members of Polish population of Adelges viridis harbor endosymbionts.•The endosymbionts occur in the cytoplasm of giant cells termed bacteriocytes.•Each bacteriocyte contains two morphotypes of bacteria.•Both morphotypes belong to the species Ca. Vallottia virida (Betaproteobacteria).•The endosymbionts are transmitted transovarially between generations.
The current data are still inconclusive in terms of a genetic component involved in the susceptibility to renal cell carcinoma. Our aim was to evaluate 40 selected candidate polymorphisms for ...potential association with clear cell renal cell carcinoma (ccRCC) based on independent group of 167 patients and 200 healthy controls. The obtained data were searched for independent effects of particular polymorphisms as well as haplotypes and genetic interactions. Association testing implied position rs4765623 in the SCARB1 gene ( OR = 1.688 , 95% CI: 1.104–2.582, P = 0.016 ) and a haplotype in VDR comprising positions rs739837, rs731236, rs7975232, and rs1544410 ( P = 0.012 ) to be the risk factors in the studied population. The study detected several epistatic effects contributing to the genetic susceptibility to ccRCC. Variation in GNAS1 was implicated in a strong synergistic interaction with BIRC5. This effect was part of a model suggested by multifactor dimensionality reduction method including also a synergy between GNAS1 and SCARB1 ( P = 0.036 ). Significance of GNAS1-SCARB1 interaction was further confirmed by logistic regression ( P = 0.041 ), which also indicated involvement of SCARB1 in additional interaction with EPAS1 ( P = 0.008 ) as well as revealing interactions between GNAS1 and EPAS1 ( P = 0.016 ), GNAS1 and MC1R ( P = 0.031 ), GNAS1 and VDR ( P = 0.032 ), and MC1R and VDR ( P = 0.035 ).
Cumuli oophori surrounding ovulated oocytes of B10.BR(Ydel) females (sired by males with the Y-chromosome long-arm deletion) are more resistant to hyaluronidase digestion than cumuli oophori around ...eggs of genetically identical females but sired by males with the intact Y chromosome (B10.BR). This has been interpreted as a result of differences in paternal genome imprinting, which females of both groups inherit from their fathers. The following study shows that it is not hyaluronan, but rather excessive protein concentration, that makes the cumulus extracellular matrix of B10.BR(Ydel) oocytes more resistant to enzymatic treatment. It was revealed, additionally, that cumulus cells around ovulating oocytes of B10.BR(Ydel) females display higher surface accumulation of prostaglandin EP2 subtype receptors and higher expression of the Ptgs2 gene (encoding a rate-limiting enzyme of prostaglandin E2 synthesis) in relation to the cells of control B10.BR females. The expression levels of the prostaglandin-dependent Tnfaip6 and Ccl2 genes were also altered in B10.BR(Ydel) cumulus cells in a manner indicating increased prostaglandin signalling. The study provides further evidence for the divergence in reproductive phenotypes between B10.BR and B10.BR(Ydel) female mice. It supports the hypothesis that genes of the Y-chromosome long arm may be involved in establishment of epigenetic marks in X-bearing spermatozoa.
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