Bortezomib restores stroma-mediated APO2L/TRAIL apoptosis resistance in multiple myeloma.

European Journal of Haematology
Lia E PerezWilliam Dalton

Abstract

Hematopoietic stroma promotes resistance to immune control by APO2L/TRAIL in multiple myeloma (MM) cells in part by increasing synthesis of the anti-apoptotic protein c-FLIP. Here, we tested whether bortezomib can reverse the APO2L/TRAIL environmental mediated-immune resistance (EM-IR). MM cell lines (RPMI 8226 and U266) and CD138+ patient's MM cells were directly adhered to HS5 stroma exposed to HS5 or bone marrow stroma of patients with MM released soluble factors in a transwell system. Cells were treated with either APO2L/TRAIL (10 ng/mL), bortezomib (10 nm) or both. Pretreatment with bortezomib effectively overcomes APO2L/TRAIL apoptosis resistance in myeloma cell lines and in CD138+ cells while directly adhered or in transwell assay. Bortezomib was not cytotoxic to HS5 stroma cells and only altered monocyte chemotactic protein-2-3 and IL-10 levels in the stroma-myeloma milieu. Factors released by HS5 stroma increased expression of c-FLIP, induced STAT-3 and ERK phosphorylation and reduced DR4 receptor expression in MM cells. HS5 stroma-released factor(s) induced NF-kappaB activation after 20 h exposure in association with an enhanced c-FLIP transcription. Bortezomib effectively reduced c-FLIP protein expression without aff...Continue Reading

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Citations

Oct 6, 2011·Apoptosis : an International Journal on Programmed Cell Death·Stephen McManusSophie Roux
Jan 15, 2014·Cellular and Molecular Life Sciences : CMLS·Chiara GaspariniGiorgio Zauli
Aug 19, 2014·Trends in Pharmacological Sciences·Sahdeo PrasadBharat B Aggarwal
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Nov 13, 2010·Cancer Letters·Sarah Shirley, Olivier Micheau
Nov 20, 2015·Pathology Oncology Research : POR·Di-Yi WangRong Zhu
Jun 10, 2014·Biochemical and Biophysical Research Communications·Fenglin ZangBaocun Sun
Feb 22, 2012·Cancers·Ahmad R Safa, Karen E Pollok
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Nov 10, 2013·Cancers·Alessandro NatoniCorrado Santocanale
Apr 1, 2015·Asian Pacific Journal of Cancer Prevention : APJCP·Samira GoldarBehzad Baradaran

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Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis