Adenovirus-mediated transfection of caspase-8 augments anoikis and inhibits peritoneal dissemination of human gastric carcinoma cells.
Adenovirus-mediated transfection of caspase-8 augments anoikis and inhibits peritoneal dissemination of human gastric carcinoma cells.
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发表时间：
2001-10
期刊：
影响因子：
11.2
通讯作者：
Susumu Nishimura;Masaaki Adachi;Tadao Ishida;Takahiro Matsunaga;Hiroaki Uchida;Hirofumi Hamada;Kohzoh Imai
中科院分区：
文献类型：
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作者：
Susumu Nishimura;Masaaki Adachi;Tadao Ishida;Takahiro Matsunaga;Hiroaki Uchida;Hirofumi Hamada;Kohzoh Imai
Caspase-8是半胱氨酸蛋白酶家族的成员，其调节由多种细胞死亡信号诱导的细胞凋亡，并且最近发现其在失巢凋亡过程中被激活，失巢凋亡是上皮细胞中锚定丧失引起的细胞凋亡的一种形式。我们以前证明，抑制失巢凋亡促进腹膜传播的人胃癌MKN 45细胞，这是锚定依赖性的。这表明失巢凋亡的增强可以抑制癌细胞的扩散。为了确定外源性过表达caspase-8是否可以增加MKN 45细胞中的失巢凋亡，我们使用腺病毒（Adv）载体（Adv-caspase-8）将caspase-8基因转染MKN 45细胞。在这里，我们证明了Adv-caspase-8感染，在15感染复数（MOI），可以增加MKN 45细胞的失巢凋亡，并抑制MKN 45在SCID小鼠的腹膜播散。对腹膜播散的抑制作用导致与对照小鼠相比延长的生存期。相比之下，Adv-caspase-8（15 MOI）对附着的MKN 45细胞或s.c. SCID小鼠的肿瘤生长。因此，Adv-mediated过度表达caspase-8主要通过增强失巢凋亡抑制腹膜播散。此外，Adv-caspase-8介导的失巢凋亡增强在另一种胃癌MKN 74细胞系中也类似地观察到。相反，Adv-p53不能增强MKN 45细胞的失巢凋亡。这些结果表明，Adv-mediated的caspase-8基因转移可以选择性地诱导脱落的癌细胞凋亡，因此，显示出潜在的作为一种新的癌症治疗对胃癌和可能其他癌细胞起源于上皮组织的传播。
Caspase-8 is a member of the cysteine protease family that modulates apoptosis induced by a variety of cell death signals and has recently been found to be activated during the process of anoikis, which is a form of apoptosis caused by loss of anchorage in epithelial cells. We previously demonstrated that the inhibition of anoikis promotes peritoneal dissemination of human gastric carcinoma MKN45 cells, which are anchorage dependent. This suggests that augmentation of anoikis may suppress dissemination of carcinoma cells. To determine whether extrinsic overexpression of caspase-8 can augment anoikis in MKN45 cells, we transfected them with the caspase-8 gene using an adenoviral (Adv) vector (Adv-caspase-8). Here we demonstrate that Adv-caspase-8 infection, at 15 multiplicity of infection (MOI), can augment anoikis in MKN45 cells and suppresses MKN45 peritoneal dissemination in SCID mice. The inhibitory effect on peritoneal dissemination resulted in a prolonged survival compared with that in control mice. In contrast, the Adv-caspase-8 (15 MOI) had no distinct effect on cell viability or growth either of attached MKN45 cells or of s.c. tumor growth in SCID mice. Thus, Adv-mediated overexpression of caspase-8 suppressed peritoneal dissemination mainly through augmentation of anoikis. In addition, Adv-caspase-8-mediated augmentation of anoikis was similarly observed in another gastric carcinoma MKN74 cell line. In contrast, Adv-p53 could not augment anoikis in MKN45 cells. These results imply that Adv-mediated gene transfer of caspase-8 can selectively induce apoptosis in detached carcinoma cells and, thus, shows potential as a novel cancer therapy against dissemination of gastric and probably other carcinoma cells originating from epithelial tissues.