title: Inhibition of TACE activity enhances the susceptibility of myeloma cells to TRAIL.
abstract: BACKGROUND
  TNF-related apoptosis-inducing ligand/Apo2 ligand (TRAIL/Apo2L) selectively induces apoptosis in various cancer cells including myeloma (MM) cells. However, the susceptibility of MM cells to TRAIL is largely low in most of MM cells by yet largely unknown mechanisms. Because TNF-α converting enzyme (TACE) can cleave some TNF receptor family members, in the present study we explored the roles of proteolytic modulation by TACE in TRAIL receptor expression and TRAIL-mediated cytotoxicity in MM cells.
  
  
  RESULTS
  MM cells preferentially expressed death receptor 4 (DR4) but not DR5 on their surface along with TACE. Conditioned media from RPMI8226 and U266 cells contained a soluble form of DR4. The DR4 levels in these conditioned media were reduced by TACE inhibition by the TACE inhibitor TAPI-0 as well as TACE siRNA. Conversely, the TACE inhibition restored surface levels of DR4 but not DR5 in these cells without affecting DR4 mRNA levels. The TACE inhibition was able to restore cell surface DR4 expression in MM cells even in the presence of bone marrow stromal cells or osteoclasts, and enhanced the cytotoxic effects of recombinant TRAIL and an agonistic antibody against DR4 on MM cells.
  
  
  CONCLUSIONS
  These results demonstrate that MM cells post-translationally down-modulate the cell surface expression of DR4 through ectodomain shedding by endogenous TACE, and that TACE inhibition is able to restore cell surface DR4 levels and the susceptibility of MM cells to TRAIL or an agonistic antibody against DR4. Thus, TACE may protect MM cells from TRAIL-mediated death through down-modulation of cell-surface DR4. It can be envisaged that TACE inhibition augments clinical efficacy of TRAIL-based immunotherapy against MM, which eventually becomes resistant to the present therapeutic modalities.
authors.affiliation: Department of Medicine and Bioregulatory Sciences, University of Tokushima Graduate School of Medicine, Tokushima, Japan.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Kagawa
authors.forename: Ayako
authors.initials: A
authors.lastname: Nakano
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Miki
authors.forename: Asuka
authors.initials: A
authors.lastname: Oda
authors.forename: Hiroe
authors.initials: H
authors.lastname: Amou
authors.forename: Kyoko
authors.initials: K
authors.lastname: Takeuchi
authors.forename: Shingen
authors.initials: S
authors.lastname: Nakamura
authors.forename: Takeshi
authors.initials: T
authors.lastname: Harada
authors.forename: Shiro
authors.initials: S
authors.lastname: Fujii
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Yata
authors.forename: Shuji
authors.initials: S
authors.lastname: Ozaki
authors.forename: Toshio
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Masahiro
authors.initials: M
authors.lastname: Abe
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000072198:ADAM17 Protein; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D005434:Flow Cytometry; D018922:HL-60 Cells; D006801:Humans; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D020298:U937 Cells
chemical_list: D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human