Inhibition of protein geranylgeranylation induces apoptosis in myeloma plasma cells by reducing Mcl-1 protein levels

Blood ◽  
2003 ◽  
Vol 102 (9) ◽  
pp. 3354-3362 ◽  
Author(s):  
Niels W. C. J. van de Donk ◽  
Marloes M. J. Kamphuis ◽  
Berris van Kessel ◽  
Henk M. Lokhorst ◽  
Andries C. Bloem
Keyword(s):  
Multiple Myeloma ◽  
Plasma Cells ◽  
Mevalonate Pathway ◽  
Cytochrome C Release ◽  
Hmg Coa Reductase ◽  
Myeloma Cells ◽  
Protein Levels ◽  
Geranylgeranyl Transferase ◽  
Induced Apoptosis ◽  
Coa Reductase

AbstractHMG-CoA reductase is the rate-limiting enzyme of the mevalonate pathway leading to the formation of cholesterol and isoprenoids such as farnesylpyrophosphate (FPP) and geranylgeranylpyrophosphate (GGPP). The inhibition of HMG-CoA reductase by lovastatin induced apoptosis in plasma cell lines and tumor cells from patients with multiple myeloma. Here we show that cotreatment with mevalonate or geranylgeranyl moieties, but not farnesyl groups, rescued myeloma cells from lovastatin-induced apoptosis. In addition, the inhibition of geranylgeranylation by specific inhibition of geranylgeranyl transferase I (GGTase I) induced the apoptosis of myeloma cells. Apoptosis triggered by the inhibition of geranylgeranylation was associated with reduction of Mcl-1 protein expression, collapse of the mitochondrial transmembrane potential, expression of the mitochondrial membrane protein 7A6, cytochrome c release from mitochondria into the cytosol, and stimulation of caspase-3 activity. These results imply that protein geranylgeranylation is critical for regulating myeloma tumor cell survival, possibly through regulating Mcl-1 expression. Our results show that pharmacologic agents such as lovastatin or GGTase inhibitors may be useful in the treatment of multiple myeloma.

Expression of functional interleukin-15 receptor and autocrine production of interleukin-15 as mechanisms of tumor propagation in multiple myeloma

Blood ◽  
2000 ◽  
Vol 95 (2) ◽  
pp. 610-618 ◽  
Author(s):  
Inge Tinhofer ◽  
Ingrid Marschitz ◽  
Traudl Henn ◽  
Alexander Egle ◽  
Richard Greil
Keyword(s):  
Multiple Myeloma ◽  
Cell Survival ◽  
Cell Lines ◽  
Plasma Cells ◽  
Constitutive Expression ◽  
Myeloma Cell ◽  
Myeloma Cells ◽  
Cytotoxic Treatment ◽  
Interleukin 15 ◽  
Induced Apoptosis

Interleukin-15 (IL-15) induces proliferation and promotes cell survival of human T and B lymphocytes, natural killer cells, and neutrophils. Here we report the constitutive expression of a functional IL-15 receptor (IL-15R) in 6 of 6 myeloma cell lines and in CD38high/CD45low plasma cells belonging to 14 of 14 patients with multiple myeloma. Furthermore, we detected IL-15 transcripts in all 6 myeloma cell lines, and IL-15 protein in 4/6 cell lines and also in the primary plasma cells of 8/14 multiple myeloma patients. Our observations confirm the existence of an autocrine IL-15 loop and point to the potential paracrine stimulation of myeloma cells by IL-15 released from the cellular microenvironment. Blocking autocrine IL-15 in cell lines increased the rate of spontaneous apoptosis, and the degree of this effect was comparable to the pro-apoptotic effect of depleting autocrine IL-6 by antibody targeting. IL-15 was also capable of substituting for autocrine IL-6 in order to promote cell survival and vice versa. In short-term cultures of primary myeloma cells, the addition of IL-15 reduced the percentage of tumor cells spontaneously undergoing apoptosis. Furthermore, IL-15 lowered the responsiveness to Fas-induced apoptosis and to cytotoxic treatment with vincristine and doxorubicin but not with dexamethasone. These data add IL-15 to the list of important factors promoting survival of multiple myeloma cells and demonstrate that it can be produced and be functionally active in an autocrine manner.

Myeloid cell factor–1 is a critical survival factor for multiple myeloma

Blood ◽  
2002 ◽  
Vol 99 (6) ◽  
pp. 1885-1893 ◽  
Author(s):  
Bin Zhang ◽  
Ivana Gojo ◽  
Robert G. Fenton
Keyword(s):  
Multiple Myeloma ◽  
Cell Survival ◽  
Actinomycin D ◽  
Plasma Cells ◽  
Proteasome Inhibitors ◽  
Myeloid Cell ◽  
Caspase Activation ◽  
Protein Levels ◽  
Survival Factor ◽  
Induced Apoptosis

Abstract Multiple myeloma (MM) is characterized by the accumulation of malignant plasma cells in the bone marrow caused primarily by failure of normal homeostatic mechanisms to prevent the expansion of postgerminal center plasma cells. We have examined the molecular mechanisms that promote the survival of MM cells and have identified a key role for myeloid cell factor–1 (Mcl-1), an antiapoptotic member of the Bcl-2 family. These experiments were initiated by the observation that MM cells were exquisitely sensitive to culture in the presence of actinomycin D: caspase activation occurred within 3 hours of treatment and cells were not protected by interleukin-6, the main MM cell growth and survival factor. Actinomycin D–induced apoptosis was blocked by proteasome inhibitors, suggesting that a labile protein was required for MM cell survival. Further analysis demonstrated that Mcl-1 was likely to be the labile factor governing MM cell survival. Mcl-1 protein levels decreased rapidly after culture in the presence of actinomycin D in concordance with effector caspase activation, but addition of proteasome inhibitors reversed the loss of Mcl-1 and maintained cell viability. The levels of other antiapoptotic proteins, including Bcl-2 and members of the inhibitors-of-apoptosis family, were unaffected by these interventions. Furthermore, Mcl-1 antisense oligonucleotides caused a rapid down-regulation of Mcl-1 protein levels and the coincident induction of apoptosis, whereas overexpression of Mcl-1 delayed actinomycin D–induced apoptosis with kinetics that correlated with expression levels of Mcl-1. These data indicate that Mcl-1 expression is required for the survival of MM cells and may represent an important target for future therapeutics.

scholarly journals Mevalonate Prevents Lovastatin-Induced Apoptosis in Medulloblastoma Cell Lines

1999 ◽  
Vol 26 (4) ◽  
pp. 305-310 ◽  
Author(s):  
Wei Wang ◽  
Robert J.B. Macaulay
Keyword(s):  
Cell Lines ◽  
Mevalonate Pathway ◽  
Critical Duration ◽  
Northern Analysis ◽  
Hmg Coa Reductase ◽  
Medulloblastoma Cell ◽  
Induced Apoptosis ◽  
Coa Reductase ◽  
Medulloblastoma Cell Lines

Background:3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) is a key rate-limiting enzyme in the mevalonate pathway, which generates precursors for cholesterol biosynthesis and the production of non-steroidal mevalonate derivatives that are involved in a number of growth-regulatory processes. We have reported that lovastatin, a competitive inhibitor of HMG-CoA reductase, not only inhibits medulloblastoma proliferationin vitro, but also induces near-complete cell death via apoptosis. The present study explores some of the pathways which may be involved in lovastatin-induced apoptosis.Methods:Medulloblastoma cell lines were exposedin vitroto lovastatin with or without mevalonate, and document the effects using morphology, flow cytometry, DNA electrophoresis and Northern analysis.Results:1) Mevalonate prevents apoptosis when co-incubated with lovastatin, or when administered to lovastatin-pretreated cells. 2) Mevalonate restores the lovastatin-arrested cell cycle, allowing S phase entry. 3) Mevalonate does not prevent lovastatin-induced apoptosis after a critical duration of lovastatin pretreatment. For cell lines Daoy and UW228 this was 24 hours, and for D283 Med and D341 Med it was 48 hours. 4) Increases in HMG-CoA reductase mRNA levels induced by lovastatin are abrogated by co-incubation with lovastatin and mevalonate.Conclusion:These results confirm that lovastatin inhibition of this enzyme results in blockage of the mevalonate pathway, and that such a block is a critical step in the mechanism of lovastatin-induced apoptosis.

scholarly journals Nur77 converts phenotype of Bcl-B, an antiapoptotic protein expressed in plasma cells and myeloma

Blood ◽  
2007 ◽  
Vol 109 (9) ◽  
pp. 3849-3855 ◽  
Author(s):  
Frederic Luciano ◽  
Maryla Krajewska ◽  
Paulina Ortiz-Rubio ◽  
Stan Krajewski ◽  
Dayong Zhai ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Rna Interference ◽  
Plasma Cells ◽  
Orphan Nuclear Receptor ◽  
Myeloma Cells ◽  
Antiapoptotic Protein ◽  
Induced Apoptosis ◽  
Selective Reactivity ◽  
Rpmi 8226 ◽  
Dependent Mechanism

Abstract Defects in apoptosis mechanisms play important roles in malignancy and autoimmunity. Orphan nuclear receptor Nur77/TR3 has been demonstrated to bind antiapoptotic protein Bcl-2 and convert it from a cytoprotective to a cytodestructive protein, representing a phenotypic conversion mechanism. Of the 6 antiapoptotic human Bcl-2 family members, we found that Nur77/TR3 binds strongest to Bcl-B, showing selective reactivity with Bcl-B, Bcl-2, and Bfl-1 but not Bcl-XL, Mcl-1, or Bcl-W. Nur77 converts the phenotype of Bcl-B from antiapoptotic to proapoptotic. Bcl-B is prominently expressed in plasma cells and multiple myeloma. Endogenous Bcl-B associates with endogenous Nur77 in RPMI 8226 myeloma cells, where RNA interference experiments demonstrated dependence on Bcl-B for Nur77-induced apoptosis. Furthermore, a Nur77-mimicking peptide killed RPMI 8226 myeloma cells through a Bcl-B–dependent mechanism. Because Bcl-B is abundantly expressed in plasma cells and some myelomas, these findings raise the possibility of exploiting the Nur77/Bcl-B mechanism for apoptosis for eradication of autoimmune plasma cells or myeloma.

Amyloid Beta sharply increases HMG-CoA reductase protein levels in astrocytes isolated from C57BL/6 mice

Gene Reports ◽  
2021 ◽  
Vol 23 ◽  
pp. 101070
Author(s):  
Maryam Cheraghzadeh ◽  
Zahra Nazeri ◽  
Asma Mohammadi ◽  
Shirin Azizidoost ◽  
Mohammad Aberomand ◽  
...  
Keyword(s):  
Amyloid Beta ◽  
Hmg Coa Reductase ◽  
Protein Levels ◽  
Coa Reductase

Effects of an HMG-CoA reductase inhibitor, simvastatin, on human myeloma cells

2004 ◽  
Author(s):  
Takemi Otsuki ◽  
Haruko Sakaguchi ◽  
Tamayo Hatayama ◽  
Tomohiro Fujii ◽  
Takayuki Tsujioka ◽  
...  
Keyword(s):  
Reductase Inhibitor ◽  
Hmg Coa Reductase ◽  
Myeloma Cells ◽  
Hmg Coa Reductase Inhibitor ◽  
Coa Reductase ◽  
Human Myeloma Cells

scholarly journals Targeting the methyltransferase SETD8 impairs tumor cell survival and overcomes drug resistance independently of p53 status in multiple myeloma

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Laurie Herviou ◽  
Sara Ovejero ◽  
Fanny Izard ◽  
Ouissem Karmous-Gadacha ◽  
Claire Gourzones ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Plasma Cells ◽  
Myeloma Cell ◽  
Histone H4 ◽  
Myeloma Cells ◽  
Functional Studies ◽  
Replicative Stress ◽  
Poor Outcome ◽  
Subsequent Decrease ◽  
Lysine Methyltransferase

Abstract Background Multiple myeloma (MM) is a malignancy of plasma cells that largely remains incurable. The search for new therapeutic targets is therefore essential. In addition to a wide panel of genetic mutations, epigenetic alterations also appear as important players in the development of this cancer, thereby offering the possibility to reveal novel approaches and targets for effective therapeutic intervention. Results Here, we show that a higher expression of the lysine methyltransferase SETD8, which is responsible for the mono-methylation of histone H4 at lysine 20, is an adverse prognosis factor associated with a poor outcome in two cohorts of newly diagnosed patients. Primary malignant plasma cells are particularly addicted to the activity of this epigenetic enzyme. Indeed, the inhibition of SETD8 by the chemical compound UNC-0379 and the subsequent decrease in histone H4 methylation at lysine 20 are highly toxic in MM cells compared to normal cells from the bone marrow microenvironment. At the molecular level, RNA sequencing and functional studies revealed that SETD8 inhibition induces a mature non-proliferating plasma cell signature and, as observed in other cancers, triggers an activation of the tumor suppressor p53, which together cause an impairment of myeloma cell proliferation and survival. However, a deadly level of replicative stress was also observed in p53-deficient myeloma cells treated with UNC-0379, indicating that the cytotoxicity associated with SETD8 inhibition is not necessarily dependent on p53 activation. Consistent with this, UNC-0379 triggers a p53-independent nucleolar stress characterized by nucleolin delocalization and reduction of nucleolar RNA synthesis. Finally, we showed that SETD8 inhibition is strongly synergistic with melphalan and may overcome resistance to this alkylating agent widely used in MM treatment. Conclusions Altogether, our data indicate that the up-regulation of the epigenetic enzyme SETD8 is associated with a poor outcome and the deregulation of major signaling pathways in MM. Moreover, we provide evidences that myeloma cells are dependent on SETD8 activity and its pharmacological inhibition synergizes with melphalan, which could be beneficial to improve MM treatment in high-risk patients whatever their status for p53.

scholarly journals An inhibitor of the EGF receptor family blocks myeloma cell growth factor activity of HB-EGF and potentiates dexamethasone or anti–IL-6 antibody-induced apoptosis

Blood ◽  
2004 ◽  
Vol 103 (5) ◽  
pp. 1829-1837 ◽  
Author(s):  
Karène Mahtouk ◽  
Michel Jourdan ◽  
John De Vos ◽  
Catherine Hertogh ◽  
Geneviève Fiol ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Growth Factor ◽  
Cell Growth ◽  
Cell Lines ◽  
Stromal Cells ◽  
Egf Receptor ◽  
Myeloma Cell ◽  
Factor Activity ◽  
Myeloma Cells ◽  
Induced Apoptosis

Abstract We previously found that some myeloma cell lines express the heparin-binding epidermal growth factor–like growth factor (HB-EGF) gene. As the proteoglycan syndecan-1 is an HB-EGF coreceptor as well as a hallmark of plasma cell differentiation and a marker of myeloma cells, we studied the role of HB-EGF on myeloma cell growth. The HB-EGF gene was expressed by bone marrow mononuclear cells in 8 of 8 patients with myeloma, particularly by monocytes and stromal cells, but not by purified primary myeloma cells. Six of 9 myeloma cell lines and 9 of 9 purified primary myeloma cells expressed ErbB1 or ErbB4 genes coding for HB-EGF receptor. In the presence of a low interleukin-6 (IL-6) concentration, HB-EGF stimulated the proliferation of the 6 ErbB1+ or ErbB4+ cell lines, through the phosphatidylinositol 3-kinase/AKT (PI-3K/AKT) pathway. A pan-ErbB inhibitor blocked the myeloma cell growth factor activity and the signaling induced by HB-EGF. This inhibitor induced apoptosis of patients'myeloma cells cultured with their tumor environment. It also increased patients' myeloma cell apoptosis induced by an anti–IL-6 antibody or dexamethasone. The ErbB inhibitor had no effect on the interaction between multiple myeloma cells and stromal cells. It was not toxic for nonmyeloma cells present in patients' bone marrow cultures or for the growth of hematopoietic progenitors. Altogether, these data identify ErbB receptors as putative therapeutic targets in multiple myeloma.

Extramedullary Manifestation of Multiple Myeloma (Systemic Plasmacytoma) That Simulates Hemangioma

2000 ◽  
Vol 124 (4) ◽  
pp. 628-631
Author(s):  
Meenakshi A. Nandedkar ◽  
Susan L. Abbondanzo ◽  
Markku Miettinen
Keyword(s):  
Multiple Myeloma ◽  
Endothelial Cell ◽  
Mediastinal Mass ◽  
Epithelial Membrane Antigen ◽  
Plasma Cells ◽  
Vascular Tumor ◽  
Unique Type ◽  
Myeloma Cells ◽  
Subcutaneous Nodules ◽  
Morphologic Appearance

Abstract We describe 2 cases of a unique type of extramedullary manifestation of multiple myeloma (systemic plasmacytoma) that presented as subcutaneous nodules and mediastinal mass, respectively. Both lesions had a similar morphologic appearance, with dilated vascular-like lumina that was separated by thin fibrovascular septa, filled with erythrocytes, and lined by mature and immature plasma cells and plasmacytoid cells. The plasma and plasmacytoid lining cells showed κ light chain restriction in both cases, consistent with a B-cell monoclonal process. The lining cells were also focally positive for epithelial membrane antigen but were negative for endothelial cell markers. Abundant delicate capillaries were seen in the septa that separated the vascular lumina, mimicking a vascular tumor. Furthermore, we believe that our cases are different from the previously described blood lakes in a plasmacytoma by the presence of well-formed fibrovascular septa that separated the vascular-like spaces. Neoangiogenesis propagated by myeloma cells may contribute to this unusual morphologic manifestation of extramedullary manifestation of multiple myeloma.

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