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Inhibition of p38 mitogen-activated protein kinase unmasks a CD30-triggered apoptotic pathway in anaplastic large cell lymphoma cells

Inhibition of p38 mitogen-activated protein kinase unmasks a CD30-triggered apoptotic pathway in anaplastic large cell lymphoma cells
Inhibition of p38 mitogen-activated protein kinase unmasks a CD30-triggered apoptotic pathway in anaplastic large cell lymphoma cells
CD30, a non-death domain-containing member of the tumor necrosis factor receptor superfamily, triggers apoptosis in anaplastic large cell lymphoma cells. The CD30 signaling pathways that lead to the induction of apoptosis are poorly defined. Here, we show that the induction of apoptosis by CD30 requires concurrent inhibition of p38 mitogen-activated protein kinase, which itself is activated by engagement of CD30 with CD30 ligand. Treatment of anaplastic large cell lymphoma cells with CD30 ligand and pharmacologic inhibitors of p38 mitogen-activated protein kinase, but not with CD30 ligand or inhibitors alone, triggered the activation of caspase-8 and the induction of apoptosis. Caspase-8 activation occurred within a few hours (2.5-4 h) after receptor triggering, was unaffected by the neutralization of ligands for the death domain-containing receptors TNFR1, Fas, DR3, DR4, or DR5, but was abolished by the expression of a dominant-negative form of the adaptor protein FADD. Importantly, we show that expression of the caspase-8 inhibitor c-FLIPS is strongly induced by the CD30 ligand, and that this is dependent on the activation of p38 mitogen-activated protein kinase. Thus, we provide evidence that the induction of apoptosis by CD30 in anaplastic large cell lymphoma cells is normally circumvented by the activation of p38 mitogen-activated protein kinase. These findings have implications for CD30-targeted immunotherapy of anaplastic large cell lymphoma
t-cells, in-vitro, signaling complex, tumor-necrosis-factor, kappa-b activation, receptor family, factor superfamily, factor tnf, hodgkins-disease, caspase-8 activation, expression
1535-7163
703-711
Krysov, Sergey V.
32ce5f22-a963-4971-a6c1-befbb8a65567
Rowley, Tania F.
3a29866f-3e2c-4ee8-8fe6-fd189ac1eb3d
Al-Shamkhani, Aymen
0a40b3ce-9d71-4d41-9369-7212f0a84504
Krysov, Sergey V.
32ce5f22-a963-4971-a6c1-befbb8a65567
Rowley, Tania F.
3a29866f-3e2c-4ee8-8fe6-fd189ac1eb3d
Al-Shamkhani, Aymen
0a40b3ce-9d71-4d41-9369-7212f0a84504

Krysov, Sergey V., Rowley, Tania F. and Al-Shamkhani, Aymen (2007) Inhibition of p38 mitogen-activated protein kinase unmasks a CD30-triggered apoptotic pathway in anaplastic large cell lymphoma cells. Molecular Cancer Therapeutics, 6 (2), 703-711. (doi:10.1158/1535-7163.MCT-06-0544).

Record type: Article

Abstract

CD30, a non-death domain-containing member of the tumor necrosis factor receptor superfamily, triggers apoptosis in anaplastic large cell lymphoma cells. The CD30 signaling pathways that lead to the induction of apoptosis are poorly defined. Here, we show that the induction of apoptosis by CD30 requires concurrent inhibition of p38 mitogen-activated protein kinase, which itself is activated by engagement of CD30 with CD30 ligand. Treatment of anaplastic large cell lymphoma cells with CD30 ligand and pharmacologic inhibitors of p38 mitogen-activated protein kinase, but not with CD30 ligand or inhibitors alone, triggered the activation of caspase-8 and the induction of apoptosis. Caspase-8 activation occurred within a few hours (2.5-4 h) after receptor triggering, was unaffected by the neutralization of ligands for the death domain-containing receptors TNFR1, Fas, DR3, DR4, or DR5, but was abolished by the expression of a dominant-negative form of the adaptor protein FADD. Importantly, we show that expression of the caspase-8 inhibitor c-FLIPS is strongly induced by the CD30 ligand, and that this is dependent on the activation of p38 mitogen-activated protein kinase. Thus, we provide evidence that the induction of apoptosis by CD30 in anaplastic large cell lymphoma cells is normally circumvented by the activation of p38 mitogen-activated protein kinase. These findings have implications for CD30-targeted immunotherapy of anaplastic large cell lymphoma

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More information

Published date: 1 February 2007
Keywords: t-cells, in-vitro, signaling complex, tumor-necrosis-factor, kappa-b activation, receptor family, factor superfamily, factor tnf, hodgkins-disease, caspase-8 activation, expression

Identifiers

Local EPrints ID: 62821
URI: http://eprints.soton.ac.uk/id/eprint/62821
ISSN: 1535-7163
PURE UUID: 8607ada4-e9f4-4745-9d1b-445cfd813784
ORCID for Aymen Al-Shamkhani: ORCID iD orcid.org/0000-0003-0727-4189

Catalogue record

Date deposited: 05 Sep 2008
Last modified: 16 Mar 2024 03:02

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Contributors

Author: Sergey V. Krysov
Author: Tania F. Rowley

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