Bone marrow stroma confers resistance to Apo2 ligand/TRAIL in multiple myeloma in part by regulating c-FLIP

The Journal of Immunology : Official Journal of the American Association of Immunologists
Lia E PerezW S Dalton

Abstract

Apo2 ligand (Apo2L)/TRAIL induces apoptosis of cancer cells that express the specific receptors while sparing normal cells. Because the tumor microenvironment protects myeloma from chemotherapy, we investigated whether hemopoietic stroma induces resistance to Apo2L/TRAIL apoptosis in this disease. Apo2L/TRAIL-induced death was diminished in myeloma cell lines (RPMI 8226, U266, and MM1s) directly adhered to a human immortalized HS5 stroma cell line but not adhered to fibronectin. In a Transwell assay, with myeloma in the upper well and HS5 cells in the lower well, Apo2L/TRAIL apoptosis was reduced when compared with cells exposed to medium in the lower well. Using HS5 and myeloma patients' stroma-conditioned medium, we determined that soluble factor(s) produced by stroma-myeloma interactions are responsible for a reversible Apo2/TRAIL apoptosis resistance. Soluble factor(s) attenuated procaspase-8, procaspase-3, and poly(ADP-ribose) polymerase cleavage and diminished mitochondrial membrane potential changes without affecting Bcl-2 family proteins and/or Apo2L/TRAIL receptors. Soluble factor(s) increased the baseline levels of the anti-apoptotic protein c-FLIP in all cell lines tested. Inhibition of c-FLIP by means of RNA interfe...Continue Reading

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Citations

Jul 15, 2009·The Journal of Biological Chemistry·Yekaterina B KhotskayaRalph D Sanderson
Mar 26, 2010·Journal of Cellular Biochemistry·Ugo Testa
Oct 6, 2011·Apoptosis : an International Journal on Programmed Cell Death·Stephen McManusSophie Roux
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May 8, 2014·Médecine sciences : M/S·Lucia Borriello, Yves A DeClerck
Jan 7, 2011·Cancer Microenvironment : Official Journal of the International Cancer Microenvironment Society·Dov Zipori
Mar 1, 2013·Journal of Biomolecular Screening·Kristine MisundAnders Sundan
Nov 20, 2009·European Journal of Haematology·Lia E PerezWilliam Dalton
Nov 10, 2013·Cancers·Alessandro NatoniCorrado Santocanale
Sep 9, 2010·International Journal of Cancer. Journal International Du Cancer·Shuhong ZhangSherif S Farag
Aug 21, 2009·Nature Reviews. Cancer·Mark B MeadsWilliam S Dalton

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