Inhibition of TACE activity enhances the susceptibility of myeloma cells to TRAIL.
Inhibition of TACE activity enhances the susceptibility of myeloma cells to TRAIL.
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DOI：
10.1371/journal.pone.0031594
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Abe M
中科院分区：
文献类型：
--
作者：
Kagawa K;Nakano A;Miki H;Oda A;Amou H;Takeuchi K;Nakamura S;Harada T;Fujii S;Yata K;Ozaki S;Matsumoto T;Abe M
tnf相关凋亡诱导配体/Apo2配体（TRAIL/Apo2L）选择性诱导多种肿瘤细胞包括骨髓瘤（MM）细胞凋亡。然而，大多数MM细胞对TRAIL的易感性在很大程度上是低的，其机制尚不清楚。由于TNF-α转换酶（TACE）可以切割一些TNF受体家族成员，因此在本研究中，我们探讨了TACE在MM细胞中TRAIL受体表达和TRAIL介导的细胞毒性中的蛋白水解调节作用。MM细胞表面优先表达死亡受体4 (DR4)，而不表达死亡受体5。RPMI8226和U266细胞的条件培养基中含有可溶形式的DR4。这些条件培养基中的DR4水平因TACE抑制剂TAPI-0和TACE siRNA抑制TACE而降低。相反，在不影响DR4 mRNA水平的情况下，TACE抑制恢复了这些细胞中DR4而不是DR5的表面水平。即使在骨髓基质细胞或破骨细胞存在的情况下，TACE抑制也能恢复MM细胞表面DR4的表达，并增强了重组TRAIL和抗DR4激动抗体对MM细胞的细胞毒性作用。这些结果表明，MM细胞翻译后通过内源性TACE脱落胞外结构域下调细胞表面DR4的表达，TACE抑制能够恢复细胞表面DR4水平和MM细胞对TRAIL或DR4激动性抗体的敏感性。因此，TACE可能通过下调细胞表面DR4来保护MM细胞免受trail介导的死亡。可以设想，TACE抑制增强了基于trail的MM免疫治疗的临床疗效，MM最终对目前的治疗方式产生耐药性。
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. 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. 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.
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DOI：
10.2217/14796694.3.4.405
发表时间：
2007-08-01
期刊：
Future oncology (London, England)
影响因子：
--
作者：
Buchsbaum, Donald J;Forero-Torres, Andres;LoBuglio, Albert F
通讯作者：
LoBuglio, Albert F
影响因子：
20.3
作者：
Abe, M;Hiura, K;Matsumoto, T
通讯作者：
Matsumoto, T
影响因子：
11.4
作者：
Mizrahi, K.;Stein, J.;Askenasy, N.
通讯作者：
Askenasy, N.
影响因子：
3.2
作者：
Secchiero, Paola;Zauli, Giorgio
通讯作者：
Zauli, Giorgio
影响因子：
11.5
作者：
Tanaka, Ybichi;Abe, Masahiro;Matsumoto, Toshio
通讯作者：
Matsumoto, Toshio