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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 - Blood Cancer J (2013)

Bottom Line: 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-κB 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.

View Article: PubMed Central - PubMed

Affiliation: Faculty of Science, Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.

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-κB 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.

No MeSH data available.


Related in: MedlinePlus

Western blot analysis of bcl-2, bax, p53, p73 in HMCLs L363 (a), OPM-2 (b) and U266 (c) after Pam3CSK4 and Velcade treatment.
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fig6: Western blot analysis of bcl-2, bax, p53, p73 in HMCLs L363 (a), OPM-2 (b) and U266 (c) after Pam3CSK4 and Velcade treatment.

Mentions: Analysis at protein level indicated that TLR1/2 stimulation with Pam3CSK4 downregulated p53 and p73 proteins in L363 and OPM-2 cell lines, whereas in U266 it had no effect on p53 and p73 protein levels. Velcade and more significantly Pam3CSK4+Velcade decreased the level of p53 protein in FN-adhered and non-adhered cells. This is in contrast to the recent finding that Velcade would upregulate p53 protein in MM cells in stroma-free conditions.31 Interestingly, in all cell lines Velcade alone or its combination with Pam3CSK4 increased the level of p73 protein. Next, we analyzed BCL-2 and Bax proteins whose balance have a critical role in controlling apoptosis, with upregulation of Bax and downregulation of BCL-2 signifying an apoptotic response.43, 44 As illustrated in Figure 6, in all HMCLs stimulation with Pam3CSK4 did not change BCL-2 and Bax proteins compared with the baseline. Velcade and more significantly Pam3CSK4+Velcade downregulated both proteins. Taken all together, these findings imply that TLR-1/2 triggering could amplify the Velcade-induced expression of genes, which mostly inhibit cell cycle (cell proliferation) or control apoptosis, in part through the p53 signaling pathway.


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 - Blood Cancer J (2013)

Western blot analysis of bcl-2, bax, p53, p73 in HMCLs L363 (a), OPM-2 (b) and U266 (c) after Pam3CSK4 and Velcade treatment.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3674459&req=5

fig6: Western blot analysis of bcl-2, bax, p53, p73 in HMCLs L363 (a), OPM-2 (b) and U266 (c) after Pam3CSK4 and Velcade treatment.
Mentions: Analysis at protein level indicated that TLR1/2 stimulation with Pam3CSK4 downregulated p53 and p73 proteins in L363 and OPM-2 cell lines, whereas in U266 it had no effect on p53 and p73 protein levels. Velcade and more significantly Pam3CSK4+Velcade decreased the level of p53 protein in FN-adhered and non-adhered cells. This is in contrast to the recent finding that Velcade would upregulate p53 protein in MM cells in stroma-free conditions.31 Interestingly, in all cell lines Velcade alone or its combination with Pam3CSK4 increased the level of p73 protein. Next, we analyzed BCL-2 and Bax proteins whose balance have a critical role in controlling apoptosis, with upregulation of Bax and downregulation of BCL-2 signifying an apoptotic response.43, 44 As illustrated in Figure 6, in all HMCLs stimulation with Pam3CSK4 did not change BCL-2 and Bax proteins compared with the baseline. Velcade and more significantly Pam3CSK4+Velcade downregulated both proteins. Taken all together, these findings imply that TLR-1/2 triggering could amplify the Velcade-induced expression of genes, which mostly inhibit cell cycle (cell proliferation) or control apoptosis, in part through the p53 signaling pathway.

Bottom Line: 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-κB 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.

View Article: PubMed Central - PubMed

Affiliation: Faculty of Science, Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.

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-κB 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.

No MeSH data available.


Related in: MedlinePlus