scholarly journals The oxidative stress response regulates DKK1 expression through the JNK signaling cascade in multiple myeloma plasma cells

Blood ◽  
2007 ◽  
Vol 109 (10) ◽  
pp. 4470-4477 ◽  
Author(s):  
Simona Colla ◽  
Fenghuang Zhan ◽  
Wei Xiong ◽  
Xiaosong Wu ◽  
Hongwei Xu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Multiple Myeloma ◽  
Wnt Signaling ◽  
Plasma Cells ◽  
Cell Types ◽  
Signaling Cascade ◽  
Jnk Pathway ◽  
Jnk Signaling ◽  
Dkk1 Expression

Abstract Multiple myeloma (MM) plasma cells, but not those from healthy donors and patients with monoclonal gammopathy of undetermined significance or other plasma cell dyscrasias involving the bone marrow, express the Wnt-signaling antagonist DKK1. We previously reported that secretion of DKK1 by MM cells likely contributes to osteolytic lesions in this disease by inhibiting Wnt signaling, which is essential for osteoblast differentiation and survival. The mechanisms responsible for activation and regulation of DKK1 expression in MM are not known. Herein, we could trace DKK1 expression changes in MM cells to perturbations in the JNK signaling cascade, which is differentially modulated through oxidative stress and interactions between MM cells with osteoclasts in vitro. Despite its role as a tumor suppressor and mediator of apoptosis in other cell types including osteoblasts, our data suggest that DKK1, a stress-responsive gene in MM, does not mediate apoptotic signaling, is not activated by TP53, and its forced overexpression could not inhibit cell growth or sensitize MM cells to apoptosis following treatment with thalidomide or lenalidomide. We conclude that specific strategies to modulate persistent activation of the JNK pathway may be beneficial in preventing disease progression and treating myeloma-associated bone disease by inhibiting DKK1 expression.

scholarly journals Tumor cell heterogeneity in multiple myeloma: antigenic, morphologic, and functional studies of cells from blood and bone marrow

Blood ◽  
1989 ◽  
Vol 73 (7) ◽  
pp. 1925-1935
Author(s):  
MA King ◽  
DS Nelson
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Tumor Cell ◽  
Tumor Cells ◽  
B Lymphocytes ◽  
Plasma Cells ◽  
Bone Marrow Cells ◽  
Cell Types ◽  
Pokeweed Mitogen

Tumor cells from six patients with immunoglobulin G (IgG) multiple myeloma were analyzed for surface antigens, cytoplasmic paraprotein, morphology, and response to various culture conditions. The tumor marker was the paraprotein idiotype. Low numbers of tumor cells were found in the blood of most of the patients. In some patients, the circulating tumor cells were solely B lymphocytes, whereas in other patients, they were lymphoid, lymphoplasmacytoid, and plasmacytoid. Dual surface antigen analysis of blood and bone marrow cells confirmed that the tumor may be composed of a spectrum of cell types. Thus, cells may range from surface-idiotype+,CD19+,CD20+, PCA-1-,cytoplasmic- idiotype- lymphocytes, to CD19-,PCA-1+,cytoplasmic-idiotype+ plasma cells that are surface-idiotype- or weakly surface-idiotype+. In one patient, some of the tumor cells co-expressed surface idiotype and CD10. The tumor B lymphocytes were activated in vitro to synthesize paraprotein by pokeweed mitogen (PWM), and by low molecular weight B cell growth factor (BCGF). In contrast, spontaneous synthesis of paraprotein by more mature tumor cells was inhibited by agents that also inhibit nonmyeloma plasma cells. These agents included PWM, gamma interferon, and phorbol ester. The results demonstrate that in multiple myeloma there exist different tumor cell types that are similar, by a variety of criteria, to normal B lineage cells at different stages of differentiation. Thus, further evidence is provided for the hypothesis of myeloma cell differentiation.

scholarly journals Tumor cell heterogeneity in multiple myeloma: antigenic, morphologic, and functional studies of cells from blood and bone marrow

Blood ◽  
1989 ◽  
Vol 73 (7) ◽  
pp. 1925-1935 ◽  
Author(s):  
MA King ◽  
DS Nelson
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Tumor Cell ◽  
Tumor Cells ◽  
B Lymphocytes ◽  
Plasma Cells ◽  
Bone Marrow Cells ◽  
Cell Types ◽  
Pokeweed Mitogen

Abstract Tumor cells from six patients with immunoglobulin G (IgG) multiple myeloma were analyzed for surface antigens, cytoplasmic paraprotein, morphology, and response to various culture conditions. The tumor marker was the paraprotein idiotype. Low numbers of tumor cells were found in the blood of most of the patients. In some patients, the circulating tumor cells were solely B lymphocytes, whereas in other patients, they were lymphoid, lymphoplasmacytoid, and plasmacytoid. Dual surface antigen analysis of blood and bone marrow cells confirmed that the tumor may be composed of a spectrum of cell types. Thus, cells may range from surface-idiotype+,CD19+,CD20+, PCA-1-,cytoplasmic- idiotype- lymphocytes, to CD19-,PCA-1+,cytoplasmic-idiotype+ plasma cells that are surface-idiotype- or weakly surface-idiotype+. In one patient, some of the tumor cells co-expressed surface idiotype and CD10. The tumor B lymphocytes were activated in vitro to synthesize paraprotein by pokeweed mitogen (PWM), and by low molecular weight B cell growth factor (BCGF). In contrast, spontaneous synthesis of paraprotein by more mature tumor cells was inhibited by agents that also inhibit nonmyeloma plasma cells. These agents included PWM, gamma interferon, and phorbol ester. The results demonstrate that in multiple myeloma there exist different tumor cell types that are similar, by a variety of criteria, to normal B lineage cells at different stages of differentiation. Thus, further evidence is provided for the hypothesis of myeloma cell differentiation.

JNK Regulates DKK1 Expression in Multiple Myeloma Cells.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3411-3411
Author(s):  
Simona Colla ◽  
Fenghuang Zhan ◽  
Shmuel Yaccoby ◽  
Joshua Epstein ◽  
Bart Barlogie ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Wnt Signaling ◽  
Plasma Cells ◽  
Effective Means ◽  
Ectopic Expression ◽  
Specific Inhibitor ◽  
Osteolytic Lesions ◽  
Myeloma Cells ◽  
Dkk1 Expression

Abstract Multiple myeloma (MM), a tumor of terminally differentiated plasma cells, depends on the bone marrow for growth and survival. MM is characterized by extensive bone loss and osteolytic lesions located at the sites of medullary plasmacytomas, suggesting that myeloma cells alter the biology of bone remodeling. Wnt signaling in osteoblasts is essential for the maintenance of osteoblast and osteoclast homeostasis and thus coupled bone turnover. MM plasma cells, but not those from healthy donors or MGUS, secrete Wnt signaling inhibitors DKK1, sFRP-2 and sFRP-3. The production of these factors contributes to osteolytic lesions by inhibiting Wnt signaling in the bone marrow milieu. It is currently not known how DKK1 expression is activated and regulated in MM. Here we report that DKK-1 expression is significantly lower in 45 myeloma cell lines (MMCL) and 5 secondary plasma cell leukemias/ pleural effusions compared to primary myeloma cells and down-regulated in all 9 primary myeloma cells with high DKK1 expression levels (Affymetrix Signal > 1,000) following co-culture with osteoclasts. This inhibition of DKK1 is associated with the simultaneous down-regulation of JUN, FOS, and FOSB, of which JUN has been shown to regulate DKK1 (Grotewald and Ruther, 2002). Ectopic expression of c-Jun in Jun negative MMCLs did not induce DKK1 expression, indicating that DKK1 transcription in this cell type is not solely dependent on c-Jun. DKK1 transcription increased 2- to 20-fold in myeloma cells from 21 of 42 primary MM following 48 hour of in-vivo exposure to thalidomide and 19 of 24 exposed to lenolidomide. The JNK-specific inhibitor SP600125 could significantly inhibit the up-regulation of DKK1 in 7 of 9 primary MM cells following in-vitro exposure to thalidomide or lenolidomide. Finally, treatment of MMCL and primary MM with the JNK activator Anisomycin resulted in up-regulation of DKK1 2- to 5-fold, but not in the presence of SP600125. These data indicate that DKK1 expression in MM cells is, in part, dependent on JNK signaling and suggests that JNK inhibitors may be an effective means of inhibiting both DKK1 expression and MM bone disease.

DKK1 is an Immediate Early Gene in Multiple Myeloma Cells Modulated by Cell Density and IL-6

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1928-1928 ◽  
Author(s):  
Erming Tian ◽  
Yawei Qiang ◽  
Bart Barlogie ◽  
John Shaughnessy
Keyword(s):  
Multiple Myeloma ◽  
Cell Density ◽  
Bone Disease ◽  
Time Course ◽  
Plasma Cells ◽  
Culture Media ◽  
Dkk1 Expression ◽  
Low Cell Density

Abstract Abstract 1928 Dickkopf-1 (DKK1), a soluble inhibitor of Wnt/b-catenin signaling, is actively transcribed in early embryogenesis but DKK1 expression is largely absent in adult tissues. Consistent with concept that cancer recapitulates early development, we discovered that multiple myeloma (MM) cells, but not plasma cells from normal healthy donors express and secrete DKK1. Elevated DKK1 also characterizes most solid tumors. An important link between DKK1 and osteolytic bone loss in MM and solid tumor bone metastases has now been established. Given its central role in MM pathogenesis, we studied the molecular basis of DKK1 activation in MM. DKK1 gene and protein expression is elevated in approximately 80% of newly diagnosed disease. The LB and MF molecular subtypes, with the lowest incidence of lytic bone disease, also have the lowest expression of DKK1. Interphase FISH and aCGH on over 100 cases revealed that DKK1 activation is not a result of copy number changes or mutations of the gene locus at chromosome 10q11.2. Reduced methylation of CpG islands in the DKK1 proximal promoter in a subset of primary MM was not linked to DKK1 mRNA expression. Although there is variation, there is also no significant difference in DKK1 expression in cells taken at diagnosis and relapse in 95 cases. Emerging evidence suggests that elevated DKK1 expression in MM cells is correlated with bone disease in MGUS and increased risk of progression of MGUS to MM. Thalidomide and lenalidomide, but not bortezomib induces DKK1 mRNA and protein expression in primary MM cells following in-vivo exposure and in MM cell lines (MMCL) in-vitro. Consistent with DKK1 gene expression being actively modulated, we discovered that DKK1 levels were significantly different in RNA isolated from the INA6 MMCL obtained from different laboratories. We used RT-PCR in a time course experiment to show that DKK1 mRNA levels spiked greater than 10-fold within minutes of adding the cells to fresh culture media. These levels were maintained for several hours and then rapidly dropped to basal levels for the remainder of the 3-day culture period. Comparable results were obtained when CD138+ selected cells from primary disease were cultured in fresh media. In contrast to the spike in DKK1 mRNA, ELISA of culture supernatants revealed that DKK1 protein levels rose steadily throughout the time course. DKK1 spikes of comparable magnitude occurred in PCR-based DKK1-positive (INA6+ and M144) and DKK1-negative (OPM1 and L363) MMCL, using the day three level as a comparator. To explore if the upregulation of DKK1 following a change in culture media might be related a change in cell density, DKK1 was measured in INA6 cells cultured at varying initial cell concentrations. Interestingly, co-culture of MMCL with as little as 1ng/ml of IL6 could significantly reduce the DKK1 spike induced by low cell density. Taken together these data suggests that DKK1 expression in MM cells, and perhaps other cancer cells, is very dynamic. DKK1 spikes induced by low MM cell density in vitro may be recapitulating what metastatic cancer cells do in vivo. We suspect that high DKK1 production by plasma cells at low cell density ensures that local MSC proliferate, at the expense of osteoblast differentiation, and produce IL6, which will, depending on the MM cell density and the concentration of IL6 (reflecting MSC pool size), in turn downregulate DKK1 expression in tumor cells. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models

2021 ◽  
Vol 22 (4) ◽  
pp. 1514 ◽  
Author(s):  
Akihiro Yachie
Keyword(s):  
Oxidative Stress ◽  
Animal Models ◽  
Heme Oxygenase ◽  
Inflammatory Diseases ◽  
Cell Types ◽  
Pharmacological Intervention ◽  
Heme Oxygenase 1 ◽  
Inflammatory Reactions

Since Yachie et al. reported the first description of human heme oxygenase (HO)-1 deficiency more than 20 years ago, few additional human cases have been reported in the literature. A detailed analysis of the first human case of HO-1 deficiency revealed that HO-1 is involved in the protection of multiple tissues and organs from oxidative stress and excessive inflammatory reactions, through the release of multiple molecules with anti-oxidative stress and anti-inflammatory functions. HO-1 production is induced in vivo within selected cell types, including renal tubular epithelium, hepatic Kupffer cells, vascular endothelium, and monocytes/macrophages, suggesting that HO-1 plays critical roles in these cells. In vivo and in vitro studies have indicated that impaired HO-1 production results in progressive monocyte dysfunction, unregulated macrophage activation and endothelial cell dysfunction, leading to catastrophic systemic inflammatory response syndrome. Data from reported human cases of HO-1 deficiency and numerous studies using animal models suggest that HO-1 plays critical roles in various clinical settings involving excessive oxidative stress and inflammation. In this regard, therapy to induce HO-1 production by pharmacological intervention represents a promising novel strategy to control inflammatory diseases.

scholarly journals Bioactive Compounds from Herbal Medicine Targeting Multiple Myeloma

2021 ◽  
Vol 11 (10) ◽  
pp. 4451
Author(s):  
Coralia Cotoraci ◽  
Alina Ciceu ◽  
Alciona Sasu ◽  
Eftimie Miutescu ◽  
Anca Hermenean
Keyword(s):  
Multiple Myeloma ◽  
Survival Rate ◽  
Plasma Cells ◽  
Inhibition Of Proliferation ◽  
In Vivo Experiments ◽  
Clonal Proliferation ◽  
Hematological Cancers ◽  
Monoclonal Proteins

Multiple myeloma (MM) is one of the most widespread hematological cancers. It is characterized by a clonal proliferation of malignant plasma cells in the bone marrow and by the overproduction of monoclonal proteins. In recent years, the survival rate of patients with multiple myeloma has increased significantly due to the use of transplanted stem cells and of the new therapeutic agents that have significantly increased the survival rate, but it still cannot be completely cured and therefore the development of new therapeutic products is needed. Moreover, many patients have various side effects and face the development of drug resistance to current therapies. The purpose of this review is to highlight the bioactive active compounds (flavonoids) and herbal extracts which target dysregulated signaling pathway in MM, assessed by in vitro and in vivo experiments or clinical studies, in order to explore their healing potential targeting multiple myeloma. Mechanistically, they demonstrated the ability to promote cell cycle blockage and apoptosis or autophagy in cancer cells, as well as inhibition of proliferation/migration/tumor progression, inhibition of angiogenesis in the tumor vascular network. Current research provides valuable new information about the ability of flavonoids to enhance the apoptotic effects of antineoplastic drugs, thus providing viable therapeutic options based on combining conventional and non-conventional therapies in MM therapeutic protocols.

scholarly journals Crosstalk between endoplasmic reticulum stress and oxidative stress: a dynamic duo in multiple myeloma

2021 ◽  
Author(s):  
Sinan Xiong ◽  
Wee-Joo Chng ◽  
Jianbiao Zhou
Keyword(s):  
Oxidative Stress ◽  
Multiple Myeloma ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Cell Fate ◽  
Stress Responses ◽  
Plasma Cells ◽  
Reactive Oxygen Species Generation ◽  
Future Research ◽  
And Oxidative Stress

AbstractUnder physiological and pathological conditions, cells activate the unfolded protein response (UPR) to deal with the accumulation of unfolded or misfolded proteins in the endoplasmic reticulum. Multiple myeloma (MM) is a hematological malignancy arising from immunoglobulin-secreting plasma cells. MM cells are subject to continual ER stress and highly dependent on the UPR signaling activation due to overproduction of paraproteins. Mounting evidence suggests the close linkage between ER stress and oxidative stress, demonstrated by overlapping signaling pathways and inter-organelle communication pivotal to cell fate decision. Imbalance of intracellular homeostasis can lead to deranged control of cellular functions and engage apoptosis due to mutual activation between ER stress and reactive oxygen species generation through a self-perpetuating cycle. Here, we present accumulating evidence showing the interactive roles of redox homeostasis and proteostasis in MM pathogenesis and drug resistance, which would be helpful in elucidating the still underdefined molecular pathways linking ER stress and oxidative stress in MM. Lastly, we highlight future research directions in the development of anti-myeloma therapy, focusing particularly on targeting redox signaling and ER stress responses.

scholarly journals Hypoxia-induced CREB cooperates MMSET to modify chromatin and promote DKK1 expression in multiple myeloma

Oncogene ◽  
2021 ◽  
Author(s):  
Yinyin Xu ◽  
Jing Guo ◽  
Jing Liu ◽  
Ying Xie ◽  
Xin Li ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Combined Treatment ◽  
Hypoxia Inducible Factor ◽  
Bone Destruction ◽  
Bone Lesions ◽  
Myeloma Cells ◽  
Downstream Target ◽  
Dkk1 Expression

AbstractMyeloma cells produce excessive levels of dickkopf-1 (DKK1), which mediates the inhibition of Wnt signaling in osteoblasts, leading to multiple myeloma (MM) bone disease. Nevertheless, the precise mechanisms underlying DKK1 overexpression in myeloma remain incompletely understood. Herein, we provide evidence that hypoxia promotes DKK1 expression in myeloma cells. Under hypoxic conditions, p38 kinase phosphorylated cAMP-responsive element-binding protein (CREB) and drove its nuclear import to activate DKK1 transcription. In addition, high levels of DKK1 were associated with the presence of focal bone lesions in patients with t(4;14) MM, overexpressing the histone methyltransferase MMSET, which was identified as a downstream target gene of hypoxia-inducible factor (HIF)-1α. Furthermore, we found that CREB could recruit MMSET, leading to the stabilization of HIF-1α protein and the increased dimethylation of histone H3 at lysine 36 on the DKK1 promoter. Knockdown of CREB in myeloma cells alleviated the suppression of osteoblastogenesis by myeloma-secreted DKK1 in vitro. Combined treatment with a CREB inhibitor and the hypoxia-activated prodrug TH-302 (evofosfamide) significantly reduced MM-induced bone destruction in vivo. Taken together, our findings reveal that hypoxia and a cytogenetic abnormality regulate DKK1 expression in myeloma cells, and provide an additional rationale for the development of therapeutic strategies that interrupt DKK1 to cure MM.

scholarly journals Pterostilbene Inhibits Human Multiple Myeloma Cells via ERK1/2 and JNK Pathway In Vitro and In Vivo

2016 ◽  
Vol 17 (11) ◽  
pp. 1927 ◽  
Author(s):  
Bingqian Xie ◽  
Zhijian Xu ◽  
Liangning Hu ◽  
Gege Chen ◽  
Rong Wei ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Jnk Pathway ◽  
Myeloma Cells ◽  
Human Multiple Myeloma

scholarly journals IL-32 is a metabolic regulator promoting survival and proliferation of malignant plasma cells

2021 ◽  
Author(s):  
Kristin Roseth Aass ◽  
Robin Mjelle ◽  
Martin H. Kastnes ◽  
Synne S. Tryggestad ◽  
Luca M. van den Brink ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Oxidative Phosphorylation ◽  
Plasma Cells ◽  
Inflammatory Diseases ◽  
Mitochondrial Respiratory Chain ◽  
Gene Signature ◽  
Growth And Survival ◽  
Novel Concept

AbstractIL-32 is a non-classical cytokine expressed in cancers, inflammatory diseases and infections. IL-32 can have both extracellular and intracellular functions, and its receptor is not identified. We here demonstrate that endogenously expressed, intracellular IL-32 binds to components of the mitochondrial respiratory chain and promotes oxidative phosphorylation. Knocking out IL-32 in malignant plasma cells significantly reduced survival and proliferation in vitro and in vivo. High throughput transcriptomic and MS-metabolomic profiling of IL-32 KO cells revealed that loss of IL-32 leads to profound perturbations in metabolic pathways, with accumulation of lipids, pyruvate precursors and citrate, indicative of reduced mitochondrial function. IL-32 is expressed in a subgroup of multiple myeloma patients with an inferior prognosis. Primary myeloma cells expressing IL-32 were characterized by a plasma cell gene signature associated with immune activation, proliferation and oxidative phosphorylation. We propose a novel concept for regulation of metabolism by an intracellular cytokine and identify IL-32 as an endogenous growth and survival factor for malignant plasma cells. IL-32 is a potential prognostic biomarker and a treatment target in multiple myeloma.

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