Gibson Erika M, Henson Elizabeth S, Haney Neil, Villanueva Jacylyn, Gibson Spencer B
Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, Manitoba, Canada R3E 0V9.
Cancer Res. 2002 Jan 15;62(2):488-96.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in combination with chemotherapeutic drugs induces a synergistic apoptotic response in cancer cells. TRAIL death receptors have also been implicated in chemotherapeutic drug-induced apoptosis. This has lead to TRAIL being proposed as a potential cancer treatment. In nude mice injected with human tumors, TRAIL reduces the size of these tumors without toxic side effects. We demonstrate that the epidermal growth factor (EGF) stimulation of human embryonic kidney cells HEK 293 and breast cancer cell line MDA MB 231 effectively protects these cells from TRAIL-induced apoptosis in a dose-dependent manner. This stimulation blocks apoptosis by inhibiting TRAIL-mediated cytochrome c release from the mitochondria and caspase 3-like activation. EGF survival response involves the activation of AKT. Expression of activated AKT was sufficient to block TRAIL-induced apoptosis, and kinase-inactive AKT expression blocked EGF-protective response. In contrast, inhibition of EGF stimulation of extracellular-regulated kinase (ERK) activity did not affect EGF protection. These findings indicate that EGF receptor activation provides a survival response against TRAIL-induced apoptosis by inhibiting mitochondrial cytochrome c release that is mediated by AKT activation in epithelial-derived cells.
肿瘤坏死因子相关凋亡诱导配体（TRAIL）与化疗药物联合使用可在癌细胞中诱导协同凋亡反应。TRAIL死亡受体也与化疗药物诱导的凋亡有关。这使得TRAIL被提议作为一种潜在的癌症治疗方法。在注射了人类肿瘤的裸鼠中，TRAIL可减小这些肿瘤的大小且无毒性副作用。我们证明，表皮生长因子（EGF）对人胚肾细胞HEK 293和乳腺癌细胞系MDA MB 231的刺激能以剂量依赖的方式有效保护这些细胞免受TRAIL诱导的凋亡。这种刺激通过抑制TRAIL介导的细胞色素c从线粒体释放以及半胱天冬酶3样激活来阻断凋亡。EGF的存活反应涉及AKT的激活。活化的AKT表达足以阻断TRAIL诱导的凋亡，而激酶失活的AKT表达则阻断了EGF的保护反应。相反，抑制EGF对细胞外调节激酶（ERK）活性的刺激并不影响EGF的保护作用。这些发现表明，EGF受体激活通过抑制上皮来源细胞中由AKT激活介导的线粒体细胞色素c释放，提供了针对TRAIL诱导凋亡的存活反应。
