Stimulation of Toll-like receptor-1/2 combined with Velcade increases cytotoxicity to human multiple myeloma cells

J. Abdi, T. Mutis, J. Garssen, F. Redegeld

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

An increasing body of evidence supports the important role of adhesion to bone marrow microenvironment components for survival and drug resistance of multiple myeloma (MM) cells. Previous studies suggested that stimulation of Toll-like receptors by endogenous ligands released during inflammation and tissue damage may be pro-tumorigenic, but no studies have been performed in relation to modulation of cell adhesion and drug cytotoxicity. Here, we investigated the effect of TLR1/2 activation on adhesion of human myeloma cells to fibronectin, and their sensitivity to the proteasome inhibitor Velcade. It was found that TLR1/2 activation with Pam3CSK4 increased the cytotoxicity of Velcade in L363, OPM-2 and U266 human myeloma cells. This effect was not related to a decreased adhesion of the cells to fibronectin, but TLR1/2 activation stimulated the caspase-3 activity in Velcade-treated myeloma cells, which may be responsible for the enhanced cell death. Inhibitors of NF-kB and MAPK reduced the stimulatory effect. These findings indicate that TLR activation of MM cells could bypass protective effects of cell adhesion and suggest that TLR signaling may also have antitumorigenic potential.

Original languageEnglish
Article numbere119
JournalBlood cancer journal
Volume3
Issue number5
DOIs
Publication statusPublished - 1 May 2013

Cite this

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title = "Stimulation of Toll-like receptor-1/2 combined with Velcade increases cytotoxicity to human multiple myeloma cells",
abstract = "An increasing body of evidence supports the important role of adhesion to bone marrow microenvironment components for survival and drug resistance of multiple myeloma (MM) cells. Previous studies suggested that stimulation of Toll-like receptors by endogenous ligands released during inflammation and tissue damage may be pro-tumorigenic, but no studies have been performed in relation to modulation of cell adhesion and drug cytotoxicity. Here, we investigated the effect of TLR1/2 activation on adhesion of human myeloma cells to fibronectin, and their sensitivity to the proteasome inhibitor Velcade. It was found that TLR1/2 activation with Pam3CSK4 increased the cytotoxicity of Velcade in L363, OPM-2 and U266 human myeloma cells. This effect was not related to a decreased adhesion of the cells to fibronectin, but TLR1/2 activation stimulated the caspase-3 activity in Velcade-treated myeloma cells, which may be responsible for the enhanced cell death. Inhibitors of NF-kB and MAPK reduced the stimulatory effect. These findings indicate that TLR activation of MM cells could bypass protective effects of cell adhesion and suggest that TLR signaling may also have antitumorigenic potential.",
keywords = "Apoptosis, Fibronectin, Multiple myeloma, Pam3CSK4, Toll-like receptor, Velcade",
author = "J. Abdi and T. Mutis and J. Garssen and F. Redegeld",
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Stimulation of Toll-like receptor-1/2 combined with Velcade increases cytotoxicity to human multiple myeloma cells. / Abdi, J.; Mutis, T.; Garssen, J.; Redegeld, F.

In: Blood cancer journal, Vol. 3, No. 5, e119, 01.05.2013.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Stimulation of Toll-like receptor-1/2 combined with Velcade increases cytotoxicity to human multiple myeloma cells

AU - Abdi, J.

AU - Mutis, T.

AU - Garssen, J.

AU - Redegeld, F.

PY - 2013/5/1

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N2 - An increasing body of evidence supports the important role of adhesion to bone marrow microenvironment components for survival and drug resistance of multiple myeloma (MM) cells. Previous studies suggested that stimulation of Toll-like receptors by endogenous ligands released during inflammation and tissue damage may be pro-tumorigenic, but no studies have been performed in relation to modulation of cell adhesion and drug cytotoxicity. Here, we investigated the effect of TLR1/2 activation on adhesion of human myeloma cells to fibronectin, and their sensitivity to the proteasome inhibitor Velcade. It was found that TLR1/2 activation with Pam3CSK4 increased the cytotoxicity of Velcade in L363, OPM-2 and U266 human myeloma cells. This effect was not related to a decreased adhesion of the cells to fibronectin, but TLR1/2 activation stimulated the caspase-3 activity in Velcade-treated myeloma cells, which may be responsible for the enhanced cell death. Inhibitors of NF-kB and MAPK reduced the stimulatory effect. These findings indicate that TLR activation of MM cells could bypass protective effects of cell adhesion and suggest that TLR signaling may also have antitumorigenic potential.

AB - An increasing body of evidence supports the important role of adhesion to bone marrow microenvironment components for survival and drug resistance of multiple myeloma (MM) cells. Previous studies suggested that stimulation of Toll-like receptors by endogenous ligands released during inflammation and tissue damage may be pro-tumorigenic, but no studies have been performed in relation to modulation of cell adhesion and drug cytotoxicity. Here, we investigated the effect of TLR1/2 activation on adhesion of human myeloma cells to fibronectin, and their sensitivity to the proteasome inhibitor Velcade. It was found that TLR1/2 activation with Pam3CSK4 increased the cytotoxicity of Velcade in L363, OPM-2 and U266 human myeloma cells. This effect was not related to a decreased adhesion of the cells to fibronectin, but TLR1/2 activation stimulated the caspase-3 activity in Velcade-treated myeloma cells, which may be responsible for the enhanced cell death. Inhibitors of NF-kB and MAPK reduced the stimulatory effect. These findings indicate that TLR activation of MM cells could bypass protective effects of cell adhesion and suggest that TLR signaling may also have antitumorigenic potential.

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