Pim2 is required for maintaining multiple myeloma cell growth through modulating TSC2 phosphorylation.
Ontology highlight
ABSTRACT:
SUBMITTER: Lu J
PROVIDER: S-EPMC3953014 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:To determine the effect of overexpression PHF19 in ARP1 myeloma cells Drug resistance is a major reason for the recurrence of multiple myeloma (MM). In addition to genetic mutations, epigenetic abnormalities are involved in the whole process of MM relapse and drug resistance. In this study, we investigate the roles of polycomb like protein 19 (PHF19), a critical gene involved in the epigenetic regulation of gene expression, in the development of MM. The gene expression profiling (GEP) data shows that PHF19 is significantly up-regulated in MM cells and associated with shortened progression-free survival and overall survival in MM patients. PHF19 promotes MM cell growth both in vitro and in a subcutaneous xenograft mouse model. Up-regulated PHF19 is also associated with the development of resistance to multiple drugs, including bortezomib, in MM cells. Moreover, miR-15a can directly target PHF19 by binding to its 3'-UTR. Since miR-15a is down-regulated in MM cells, PHF19 is considered to be up-regulated due to loss of the suppression by miR-15a. The mechanistic investigations indicate that PHF19 can activate AKT which in turn leads to an increase in the phosphorylation of EZH2, a core component of PRC2 that mediates the histone H3K27 methylation. Subsequently suppresses histone H3K27 methylation and causes up-regulated expression of several anti-apoptotic genes, including BCL-xL, MCL-1 and HIF-1alpha. Moreover, PDK1 activation is significantly increased in PHF19 overexpressing MM cells.
2020-03-31 | GSE128406 | GEO
Project description:The PIM kinase family (PIM1, 2 and 3) have a central role in integrating growth and survival signals, and are expressed in a wide range of solid and hematological malignancies. We now confirm that PIM2 is overexpressed in multiple myeloma (MM) patients, and within MM group it is overexpressed in the high-risk MF subset (activation of proto-oncogenes MAF/MAFB). This is consistent with our finding of PIM2's role in key signaling pathways (IL-6, CD28 activation) that confer chemotherapy resistance in MM cells. These studies have identified a novel PIM2-selective non-ATP competitive inhibitor (JP11646) that has a 4 to 760-fold greater suppression of MM proliferation and viability than ATP-competitive PIM inhibitors. This increased efficacy is due not only to the inhibition of PIM2 kinase activity, but also to a novel mechanism involving specific downregulation of PIM2 mRNA and protein expression not seen with the ATP competitive inhibitors. Treatment with JP11646 in xenogeneic myeloma murine models demonstrated significant reduction in tumor burden and increased median survival. Altogether our findings suggest the existence of previously unrecognized feedback loop(s) where PIM2 kinase activity regulates PIM2 gene expression in malignant cells, and that JP11646 represents a novel class of PIM2 inhibitors that interdicts this feedback.
| S-EPMC5537056 | biostudies-literature
Project description:Multiple myeloma (MM) is an incurable hematologic malignancy due to inevitable relapse and chemoresistance development. Our preliminary data show that MM cells express high levels of PGC1? and LDHA. In this study, we investigated the mechanism behind PGC1?-mediated LDHA expression and its contribution to tumorigenesis, to aid in the development of novel therapeutic approaches for MM. Real-time PCR and western blotting were first used to evaluate gene expression of PGC1? and LDHA in different MM cells, and then, luciferase reporter assay, chromatin immunoprecipitation, LDHA deletion report vectors, and siRNA techniques were used to investigate the mechanism underlying PGC1?-induced LDHA expression. Furthermore, knockdown cell lines and lines stably overexpressing PGC1? or LDHA lentivirus were established to evaluate in vitro glycolysis metabolism, mitochondrial function, reactive oxygen species (ROS) formation, and cell proliferation. In addition, in vivo xenograft tumor development studies were performed to investigate the effect of PGC1? or LDHA expression on tumor growth and mouse survival. We found that PGC1? and LDHA are highly expressed in different MM cells and LDHA is upregulated by PGC1? through the PGC1?/RXR? axis acting on the LDHA promoter. Overexpression of PGC1? or LDHA significantly potentiated glycolysis metabolism with increased cell proliferation and tumor growth. On the other hand, knockdown of PGC1? or LDHA largely suppressed glycolysis metabolism with increased ROS formation and apoptosis rate, in addition to suppressing tumor growth and enhancing mouse survival. This is the first time the mechanism underlying PGC1?-mediated LDHA expression in multiple myeloma has been identified. We conclude that PGC1? regulates multiple myeloma tumor growth through LDHA-mediated glycolytic metabolism. Targeting the PGC1?/LDHA pathway may be a novel therapeutic strategy for multiple myeloma treatment.
| S-EPMC6120252 | biostudies-literature
Project description:BackgroundMultiple myeloma (MM) accounts for 10% of all hematological malignancies. Dysregulation of microRNAs (miRNAs) or long non-coding RNAs (lncRNAs) has important impacts on progression of MM. Circular RNAs (circRNAs) are correlated with malignancy in the modulation of tumor progression. This study aims to investigate the effect of circ_0000190 on regulating the progression of MM.MethodMicroscopic examination via single molecule fluorescent in situ hybridization indicates the location of circ_0000190. qRT-PCR and Western blot were used to evaluate the expression of RNAs and proteins. Potential target of circ_0000190 was searched as miRNA, and examined by luciferase reporter assay. A computational screen was also conducted to search the potential target of miRNA. In vitro cell viability, proliferation, apoptosis assays and flow cytometric were performed to assess the effects of circ_0000190 and its target on MM. Mice model of human MM was established with subcutaneous xenograft tumor, qRT-PCR and western blot were performed to detect the underlying mechanisms of circ_0000190 on MM.ResultsCirc_0000190 was located in the cytoplasm, and down-regulated in both bone marrow tissue and peripheral blood, while the target of circ_0000190, miR-767-5p, was up-regulated, suggesting a negative correlation between them. The binding ability between circ_0000190 and miR-767-5p was confirmed by luciferase reporter assay. Moreover, circ_0000190 inhibited cell viability, proliferation and induced apoptosis of MM thus inhibiting cell progression, which is partially through the negative regulation of miR-767-5p. Mitogen-activated protein kinase 4 (MAPK4) is a direct target of miR-767-5p. In addition, over-expression of miR-767-5p promoted cell progression by directly targeting and regulating MAPK4. The MM model mice with administration of circ_0000190 suppressed tumor growth and progression.ConclusionOur results revealed that the ability of circ_0000190 to protect against MM was inherited through repression of miR-767-5p, and miR-767-5p might be a tumor drive through targeting MAPK4. Therefore, a novel role of circ_0000190 on regulating the progression of MM was found, and the clinical application of circRNAs might represent a strategy in MM.
| S-EPMC6364482 | biostudies-literature
Project description:Recently, it was discovered that serglycin, a hematopoietic cell proteoglycan, is the major proteoglycan expressed and constitutively secreted by multiple myeloma (MM) cells. High levels of serglycin are present in the bone marrow aspirates of at least 30% of newly diagnosed MM patients. However, its contribution to the pathophysiology of MM is unknown. Here, we show that serglycin knockdown (by ∼85% compared with normal levels), using lentiviral shRNA, dramatically attenuated MM tumor growth in mice with severe combined immunodeficiency. Tumors formed from cells deficient in serglycin exhibited diminished levels of hepatocyte growth factor expression and impaired development of blood vessels, indicating that serglycin may affect tumor angiogenesis. Furthermore, knockdown of serglycin significantly decreased MM cell adhesion to bone marrow stromal cells and collagen I. Even though serglycin proteoglycan does not have a transmembrane domain, flow cytometry showed that serglycin is present on the MM cell surface, and attachment to the cell surface is, at least in part, dependent on its chondroitin sulfate side chains. Co-precipitation of serglycin from conditioned medium of MM cells using a CD44-Fc chimera suggests that CD44 is the cell surface-binding partner for serglycin, which therefore may serve as a major ligand for CD44 at various stages during myeloma progression. Finally, we demonstrate that serglycin mRNA expression in MM cells is up-regulated by activin, a predominant cytokine among those increased in MM patients with osteolytic lesions. These studies provide direct evidence for a critical role for serglycin in MM pathogenesis and show that targeting serglycin may provide a novel therapeutic approach for MM.
| S-EPMC3937626 | biostudies-literature
Project description:The PIM kinase family (PIM1, 2 and 3) play a central role in integrating growth and survival signals, and are expressed in a wide range of solid and hematological malignancies. We now confirm that PIM2 is overexpressed in multiple myeloma (MM) patients, and within MM group it is overexpressed in the high-risk MF subset (activation of proto-oncogenes MAF/MAFB). This is consistent with our finding of PIM2’s role in key signaling pathways (IL-6, CD28 activation) that confer chemotherapy resistance in MM cells. These studies have identified a novel PIM2-selective non-ATP competitive inhibitor (JP11646) that has a 4 to 760-fold greater suppression of MM proliferation and viability than ATP-competitive PIM inhibitors. This increased efficacy is due not only to the inhibition of PIM2 kinase activity, but also to a novel mechanism involving specific downregulation of PIM2 mRNA and protein expression not seen with the ATP competitive inhibitors. To better understand Off target effects of JP11646 and specific genes that have been directly or indirectly affected by JP11646, MM cell lines MM.1S and U266 were treated with JP11646 and then gene expression was analyzed.
2017-01-01 | GSE89812 | GEO
Project description:Hexokinase-II (HK2) is a key enzyme involved in glycolysis, which is required for breast cancer progression. However, the underlying post-translational mechanisms of HK2 activity are poorly understood. Here, we showed that Proviral Insertion in Murine Lymphomas 2 (PIM2) directly bound to HK2 and phosphorylated HK2 on Thr473. Biochemical analyses demonstrated that phosphorylated HK2 Thr473 promoted its protein stability through the chaperone-mediated autophagy (CMA) pathway, and the levels of PIM2 and pThr473-HK2 proteins were positively correlated with each other in human breast cancer. Furthermore, phosphorylation of HK2 on Thr473 increased HK2 enzyme activity and glycolysis, and enhanced glucose starvation-induced autophagy. As a result, phosphorylated HK2 Thr473 promoted breast cancer cell growth in vitro and in vivo. Interestingly, PIM2 kinase inhibitor SMI-4a could abrogate the effects of phosphorylated HK2 Thr473 on paclitaxel resistance in vitro and in vivo. Taken together, our findings indicated that PIM2 was a novel regulator of HK2, and suggested a new strategy to treat breast cancer.
| S-EPMC6224402 | biostudies-literature
Project description:PHF19 Promotes Cell Growth and Confers Drug Resistance through EZH2 Phosphorylation in Multiple Myeloma
| PRJNA527460 | ENA
Project description:As an important member of the Argonaute protein family, PIWI-like protein 1 (PIWIL1) plays a key role in tumor cell viability. However, the exact function of PIWIL1 in multiple myeloma (MM) and the underlying mechanism remain unclear. Here, we revealed that PIWIL1 was highly expressed in myeloma cell lines and newly diagnosed MM patients, and that its expression was notably higher in refractory/relapsed MM patients. PIWIL1 promoted the proliferation of MM cells and conferred resistance to chemotherapeutic agents both in vitro and in vivo. More importantly, PIWIL1 enhanced the formation of autophagosomes, especially mitophagosomes, by disrupting mitochondrial calcium signaling and modulating mitophagy-related canonical PINK1/Parkin pathway protein components. Mitophagy/autophagy inhibitors overcome PIWIL1-induced chemoresistance. In addition, PIWIL1 overexpression increased the proportion of side population (SP) cells and upregulated the expression of the stem cell-associated genes Nanog, OCT4, and SOX2, while its inhibition resulted in opposite effects. Taken together, our findings demonstrated that PIWIL1 induced drug resistance by activating mitophagy and regulating the MM stem cell population. PIWIL1 depletion significantly overcame drug resistance and could be used as a novel therapeutic target for reversing resistance in MM patients.
| S-EPMC8784391 | biostudies-literature
Project description:Background Seaweed-derived polysaccharides (SDP) represent an attractive source of prebiotic nutraceuticals for the food and animal husbandry industry. However, the mechanism by which SDP from Enteromorpha mediates pig growth are not fully understood. This study aimed to investigate how SDP supplementation influences the growth performance and intestinal health in weaned pigs. Results In Exp. 1, 240 weaned pigs were randomly assigned to four dietary treatments and fed with a basal diet or a basal diet containing 200, 400 or 800?mg/kg SDP, respectively, in a 21-day trial. Pigs on the 400 or 800?mg/kg SDP-supplemented group had greater ADG and lower F/G ratio than those on the control group (P<0.05). In Exp. 2, 20 male weaned pigs were randomly assigned to two treatments and fed with a basal diet (CON group) or a basal diet supplemented with 400?mg/kg SDP (the optimum does from Exp. 1), in a 21-day trial. Pigs fed the SDP diet had greater ADG, the concentrations of serum IL-6 and TNF-? and the activities of glutathione peroxidase, superoxide dismutase and catalase (P<0.05), and lower F/G, diarrhea rate, as well as serum D-lactate concentrations and diamine oxidase activity (P<0.05). Moreover, dietary SDP supplementation enhanced secretory immunoglobulin A content, villus height and villous height: crypt depth ratio in small intestine, as well as the lactase and maltase activities in jejunum mucosa (P<0.05). SDP supplementation elevated the mRNA levels of inflammatory response-related genes (IL-6, TNF-?, TLR4, TLR6 and MyD88), and the mRNA and protein levels of ZO-1, claudin-1 and occludin in jejunum mucosa (P<0.05). Importantly, SDP not only increased the Lactobacillus population but also reduced the Escherichia coli population in cecum (P<0.05). Furthermore, SDP increased acetic acid and butyric acid concentrations in cecum (P<0.05). Conclusions These results not only suggest a beneficial effect of SDP on growth performance and intestinal barrier functions, but also offer potential mechanisms behind SDP-facilitated intestinal health in weaned pigs.
| S-EPMC7945339 | biostudies-literature