MEK/ERK pathway is aberrantly active in Hodgkin disease: a signaling pathway shared by CD30, CD40, and RANK that regulates cell proliferation and survival

Zheng, Bei; Fiumara, Paolo; Li, Yang V.; Georgakis, Georgios V.; Snell, Virginia; Younes, Mamoun; Vauthey, Jean Nicolas; Carbone, Antonino; Younes, Anas

doi:10.1182/blood-2002-11-3507

Cited by 188 publications

(182 citation statements)

References 54 publications

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“…The activation of CD30 by CD30L has previously been shown to cause ERK phosphorylation and NF-kB activation in HRS cell lines (29)(30)(31), and, indeed, we observed increased ERK1/2 phosphorylation and increases in the activity of the alternative NF-kB pathway upon lestaurtinib treatment in all analyzed HRS cell lines. TRAIL usually induces apoptosis in tumor cells via the TRAIL-Rassociated DISC.…”

Section: Discussionsupporting

confidence: 53%

“…CD30, a cell surface TNF receptor (TNFR) expressed by most HRS cells and HRS cell lines (28), has been shown to activate the MEK/ERK pathway and the classical and alternative NF-kB pathways upon binding of its ligand (29)(30)(31). The observed increases in ERK1/2 phosphorylation upon lestaurtinib treatment are thus most likely due to the CD30L upregulation.…”

Section: Lestaurtinib Activates the Alternative Nf-kb Pathway In Hrs mentioning

confidence: 99%

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Induction of Endoplasmic Reticulum Stress by Sorafenib and Activation of NF-κB by Lestaurtinib as a Novel Resistance Mechanism in Hodgkin Lymphoma Cell Lines

Holz

Janning

Renné

et al. 2013

Molecular Cancer Therapeutics

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Hodgkin-Reed/Sternberg (HRS) cells of classical Hodgkin lymphoma show aberrant expression and activation of several receptor tyrosine kinases (RTK) in the majority of cases. Therefore, we tested whether tyrosine kinase inhibitors (TKI) already in clinical use or late stages of clinical trials have antiproliferative effects on HRS cell lines and evaluated the targets, affected signaling pathways, and mechanisms of cell death and resistance. Sorafenib and lestaurtinib had antiproliferative effects on HRS cell lines at concentrations achievable in patients. Sorafenib inhibited platelet-derived growth factor receptor (PDGFR) a, TRKA and RON, caused decreases in total and phosphorylated amounts of several signaling molecules, and provoked caspase-3-independent cell death, most likely due to endoplasmic reticulum stress as indicated by upregulation of GADD34 and GADD153 and phosphorylation of PERK. Lestaurtinib inhibited TRKA, PDGFRa, RON, and JAK2 and had only a cytostatic effect. Besides deactivation, lestaurtinib also caused activation of signaling pathways. It caused increases in CD30L and TRAIL expression, and CD30L/CD30 signaling likely led to the observed concomitant activation of extracellular signal-regulated kinase 1/2 and the alternative NF-kB pathway. These data disclose the possible use of sorafenib for the treatment of Hodgkin lymphoma and highlight NF-kB activation as a potential novel mechanism of resistance toward TKIs.

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Section: Discussionsupporting

confidence: 53%

Section: Lestaurtinib Activates the Alternative Nf-kb Pathway In Hrs mentioning

confidence: 99%

Induction of Endoplasmic Reticulum Stress by Sorafenib and Activation of NF-κB by Lestaurtinib as a Novel Resistance Mechanism in Hodgkin Lymphoma Cell Lines

Holz

Janning

Renné

et al. 2013

Molecular Cancer Therapeutics

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“…31,32 To analyze whether in MOG-EAE under Epo treatment the activity of MEK determines the expression of Bcl-2 or Bax, we performed Western blot analysis of Bcl-2 as well as Bax immunostaining in animals treated with PD 98059. These experiments revealed that Bcl-2 and Bax levels under Epo application were unaffected by inhibition of MAPK phosphorylation (Figures 3c and 4b).…”

Section: Epo-induced Regulation Of Bcl-2 and Bax Does Not Depend On Pmentioning

confidence: 99%

Neuroprotective effects and intracellular signaling pathways of erythropoietin in a rat model of multiple sclerosis

Sättler¹,

Merkler

Maier³

et al. 2004

Cell Death Differ

165

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In multiple sclerosis (MS), long-term disability is primarily caused by axonal and neuronal damage. We demonstrated in a previous study that neuronal apoptosis occurs early during experimental autoimmune encephalomyelitis, a common animal model of MS. In the present study, we show that, in rats suffering from myelin oligodendrocyte glycoprotein (MOG)-induced optic neuritis, systemic application of erythropoietin (Epo) significantly increased survival and function of retinal ganglion cells (RGCs), the neurons that form the axons of the optic nerve. We identified three independent intracellular signaling pathways involved in Epo-induced neuroprotection in vivo: Protein levels of phospho-Akt, phospho-MAPK 1 and 2, and Bcl-2 were increased under Epo application. Using a combined treatment of Epo together with a selective inhibitor of phosphatidylinositol 3-kinase (PI3-K) prevented upregulation of phospho-Akt and consecutive RGC rescue. We conclude that in MOG-EAE the PI3-K/Akt pathway has an important influence on RGC survival under systemic treatment with Epo.

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“…Studies on signaling pathways of HRS cells have implicated deregulated activation of a variety of intercellular proteins (NF-κB, Jak/STATs, Akt/mTOR, Notch-1, and ERK) as well as surface receptors (CD30 and CD40) (Clodi and Younes, 1997;Fiumara et al, 2001;Younes et al, 2003;Zheng et al, 2003), which are highly associated with pro-survival signals. Each of these proteins can be a therapeutic target of selective small molecule inhibitors.…”

Section: Hrs Cellsmentioning

confidence: 99%

Epstein-Barr Virus-Associated Classical Hodgkin Lymphoma and Its Therapeutic Strategies

Lee¹

2011

Biomolecules and Therapeutics

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Lymphoma is a type of cancer involving cells of the immune system, and has two major categories: Hodgkin lymphoma (HL) and all other lymphomas (non-HL). Although the two types may display the same symptoms, they are readily distinguishable via microscopic examination, and differ in the way they develop, spread and are treated. HL is a unique clinicopathological disorder characterized by the rare presence of malignant cells (usually accounting for 0.1% to 10% of the cells in the total tumor mass) in a background of a nonneoplastic cellular microenvironment comprising T-and Blymphocytes and other cell types (Weiss et al., 1999). In the United States, about 8,500 new cases of HL were expected to be diagnosed in 2010, and the overall incidence is increasing each year (Maggioncalda et al., 2011).Although the pathogenesis of HL is still largely unknown, the association of HL with Epstein-Barr virus (EBV) infection has been demonstrated in many reports. For examples, HL patients show elevated antibody titers to EBV antigens (Levine et al., 1971), and the risk of developing HL is increased up to three-fold in population that have experienced infectious mononucleosis caused by primary EBV infection (Gutensohn Over the past few decades, our understanding of the epidemiology and immunopathogenesis of Hodgkin lymphoma (HL) has made enormous advances. Consequently, the treatment of HL has changed signifi cantly, rendering this disease of the most curable human cancers. To date, about 80% of patients achieve long-term disease-free survival. However, therapeutic challenges still remain, particularly regarding the salvage strategies for relapsed and refractory disease, which need further identifi cation of better prognostic markers and novel therapeutic schemes. Although the precise molecular mechanism by which Epstein-Barr virus (EBV) contributes to the generation of malignant cells present in HL still remains unknown, current increasing data on the role of EBV in the pathobiology of HL have encouraged people to start developing novel and specifi c therapeutic strategies for EBVassociated HL. This review will provide an overview of therapeutic approaches for acute EBV infection and the classical form of HL (cHL), especially focusing on EBV-associated HL cases. and Cole, 1980), and EBV DNA/RNA can be detected in HL tissues (Brink et al., 1997), suggesting that as a primary event in the development of this disease, EBV infection may play a very crucial role in the pathogenesis of HL. AbstractAccording to a population-based cohort study, the frequency of EBV associated HL among total HL cases varies from 30 to 50% (in certain cases even higher; >90% in developing and underdeveloped countries, and >95% in HIV associated cases), and most of them appear in classical Hodgkin lymphoma (cHL), the major type of HL (Herbst et al., 1991;Pallesen et al., 1991;Ambinder et al., 1993;Leoncini et al., 1996). Since EBV is an oncogenic virus that is able to subvert cellular processes supporting growth and survival, the approach to unravel the f...

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MEK/ERK pathway is aberrantly active in Hodgkin disease: a signaling pathway shared by CD30, CD40, and RANK that regulates cell proliferation and survival

Cited by 188 publications

References 54 publications

Induction of Endoplasmic Reticulum Stress by Sorafenib and Activation of NF-κB by Lestaurtinib as a Novel Resistance Mechanism in Hodgkin Lymphoma Cell Lines

Induction of Endoplasmic Reticulum Stress by Sorafenib and Activation of NF-κB by Lestaurtinib as a Novel Resistance Mechanism in Hodgkin Lymphoma Cell Lines

Neuroprotective effects and intracellular signaling pathways of erythropoietin in a rat model of multiple sclerosis

Epstein-Barr Virus-Associated Classical Hodgkin Lymphoma and Its Therapeutic Strategies

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