Curtin J F, Cotter T G
Department of Biochemistry, University College Cork, Lee Maltings, Prospect Row, Cork, Ireland.
Br J Cancer. 2003 Nov 17;89(10):1950-7. doi: 10.1038/sj.bjc.6601393.
Androgen-independent prostate carcinomas are resistant to chemotherapy and cell lines derived from androgen-independent prostate carcinomas such as DU 145 cells are highly resistant to Fas-mediated apoptosis. The incubation of DU 145 cells with anti-Fas IgM agonistic antibody of Fas receptor fails to activate JNK, a stress kinase involved in regulating apoptosis. We have previously shown that JNK activation is sufficient and necessary to promote Fas-mediated apoptosis in DU 145 cells. We investigate the mechanisms by which JNK activation and apoptosis are abrogated. HSP27 is overexpressed in DU 145 cells and has previously been reported to sequester DAXX and prevent JNK activation in cells treated with anti-Fas IgM. However, we find no evidence that HSP27 interacts with DAXX in DU 145 cells. Instead, we find that FADD does not interact with caspase-8 and this results in defective death-inducing signalling complex formation following Fas receptor activation.
雄激素非依赖性前列腺癌对化疗耐药，并且源自雄激素非依赖性前列腺癌的细胞系（如DU 145细胞）对Fas介导的凋亡具有高度抗性。用Fas受体的抗Fas IgM激动抗体孵育DU 145细胞无法激活JNK，JNK是一种参与调节凋亡的应激激酶。我们之前已经表明，JNK激活对于促进DU 145细胞中Fas介导的凋亡是充分且必要的。我们研究JNK激活和凋亡被消除的机制。HSP27在DU 145细胞中过表达，并且之前有报道称其在抗Fas IgM处理的细胞中隔离DAXX并阻止JNK激活。然而，我们没有发现证据表明HSP27在DU 145细胞中与DAXX相互作用。相反，我们发现FADD不与caspase-8相互作用，这导致Fas受体激活后死亡诱导信号复合物形成缺陷。
