TNFα cooperates with IFN-γ to repress Bcl-xL expression to sensitize metastatic colon carcinoma cells to TRAIL-mediated apoptosis.
TNFα cooperates with IFN-γ to repress Bcl-xL expression to sensitize metastatic colon carcinoma cells to TRAIL-mediated apoptosis.
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DOI：
10.1371/journal.pone.0016241
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发表时间：
2011-01-17
期刊：
影响因子：
3.7
通讯作者：
Liu K
中科院分区：
文献类型：
--
作者：
Liu F;Hu X;Zimmerman M;Waller JL;Wu P;Hayes-Jordan A;Lev D;Liu K
TNF 相关凋亡诱导配体 (TRAIL) 是一种免疫效应分子，具有选择性抗肿瘤剂的作用。然而，肿瘤细胞，尤其是转移性肿瘤细胞经常表现出TRAIL耐药表型，这是目前TRAIL治疗的主要障碍。本研究的目的是探讨 TNFα 和 IFN-γ 在使转移性结肠癌细胞对 TRAIL 介导的细胞凋亡敏感中的协同作用。研究了 TNFα 和 IFN-γ 协同作用使转移性结肠癌细胞对 TRAIL 介导的细胞凋亡敏感的功效和潜在分子机制。在实验性转移小鼠模型中确定了产生 TNFα 和 IFN-γ 的 T 淋巴细胞免疫疗法联合 TRAIL 疗法在抑制结肠癌转移中的功能意义。我们观察到单独使用 TNFα 或 IFN-γ 表现出最小的致敏作用，但联合使用时可以有效地使转移性结肠癌细胞对 TRAIL 诱导的细胞凋亡敏感。 TNFα 和 IFN-γ 协同抑制 Bcl-xL 表达，而 TNFα 抑制转移性结肠癌细胞中的 Survivin 表达。沉默 Bcl-xL 表达显着增加转移性结肠癌细胞对 TRAIL 诱导的细胞凋亡的敏感性。相反，Bcl-xL 的过度表达显着降低肿瘤细胞对 TRAIL 诱导的细胞凋亡的敏感性。此外，TNFα 和 IFN-γ 还协同增强 TRAIL 诱导的 caspase-8 激活。 TNFα 和 IFN-γ 在活化的原代 T 细胞和肿瘤特异性 T 细胞中上调。 TRAIL 在体内表达于肿瘤浸润免疫细胞中，在体外表达于肿瘤特异性细胞毒性 T 淋巴细胞 (CTL) 中。因此，TRAIL疗法联合产生TNFα/IFN-γ的CTL过继转移免疫疗法可有效抑制体内结肠癌转移。 TNFα 和 IFN-γ 至少部分通过增强 caspase 8 激活和抑制 Bcl-xL 表达来合作克服 TRAIL 耐药性。 CTL免疫疗法和TRAIL疗法的联合治疗为进一步开发转移性结直肠癌的治疗带来了巨大的希望。
TNF-related apoptosis-inducing ligand (TRAIL) is an immune effector molecule that functions as a selective anti-tumor agent. However, tumor cells, especially metastatic tumor cells often exhibit a TRAIL-resistant phenotype, which is currently a major impediment in TRAIL therapy. The aim of this study is to investigate the synergistic effect of TNFα and IFN-γ in sensitizing metastatic colon carcinoma cells to TRAIL-mediated apoptosis. The efficacy and underlying molecular mechanism of cooperation between TNFα and IFN-γ in sensitizing metastatic colon carcinoma cells to TRAIL-mediated apoptosis were examined. The functional significance of TNFα- and IFN-γ-producing T lymphocyte immunotherapy in combination with TRAIL therapy in suppression of colon carcinoma metastasis was determined in an experimental metastasis mouse model. We observed that TNFα or IFN-γ alone exhibits minimal sensitization effects, but effectively sensitized metastatic colon carcinoma cells to TRAIL-induced apoptosis when used in combination. TNFα and IFN-γ cooperate to repress Bcl-xL expression, whereas TNFα represses Survivin expression in the metastatic colon carcinoma cells. Silencing Bcl-xL expression significantly increased the metastatic colon carcinoma cell sensitivity to TRAIL-induced apoptosis. Conversely, overexpression of Bcl-xL significantly decreased the tumor cell sensitivity to TRAIL-induced apoptosis. Furthermore, TNFα and IFN-γ also synergistically enhanced TRAIL-induced caspase-8 activation. TNFα and IFN-γ was up-regulated in activated primary and tumor-specific T cells. TRAIL was expressed in tumor-infiltrating immune cells in vivo, and in tumor-specific cytotoxic T lymphocytes (CTL) ex vivo. Consequently, TRAIL therapy in combination with TNFα/IFN-γ-producing CTL adoptive transfer immunotherapy effectively suppressed colon carcinoma metastasis in vivo. TNFα and IFN-γ cooperate to overcome TRAIL resistance at least partially through enhancing caspase 8 activation and repressing Bcl-xL expression. Combined CTL immunotherapy and TRAIL therapy hold great promise for further development for the treatment of metastatic colorectal cancer.
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