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首页> 外文期刊>Cell death & disease. >Proteasomal inhibition sensitizes cervical cancer cells to mitomycin C-induced bystander effect: the role of tumor microenvironment
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Proteasomal inhibition sensitizes cervical cancer cells to mitomycin C-induced bystander effect: the role of tumor microenvironment

机译：蛋白酶体抑制作用使宫颈癌细胞对丝裂霉素C诱导的旁观者效应敏感：肿瘤微环境的作用

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Inaccessibility of drugs to poorly vascularized strata of tumor is one of the limiting factors in cancer therapy. With the advent of bystander effect (BE), it is possible to perpetuate the cellular damage from drug-exposed cells to the unexposed ones. However, the role of infiltrating tumor-associated macrophages (TAMs), an integral part of the tumor microenvironment, in further intensifying BE remains obscure. In the present study, we evaluated the effect of mitomycin C (MMC), a chemotherapeutic drug, to induce BE in cervical carcinoma. By using cervical cancer cells and differentiated macrophages, we demonstrate that MMC induces the expression of FasL via upregulation of PPAR γ in both cell types (effector cells) in vitro , but it failed to induce bystander killing in cervical cancer cells. This effect was primarily owing to the proteasomal degradation of death receptors in the cervical cancer cells. Pre-treatment of cervical cancer cells with MG132, a proteasomal inhibitor, facilitates MMC-mediated bystander killing in co-culture and condition medium transfer experiments. In NOD/SCID mice bearing xenografted HeLa tumors administered with the combination of MMC and MG132, tumor progression was significantly reduced in comparison with those treated with either agent alone. FasL expression was increased in TAMs, and the enhanced level of Fas was observed in these tumor sections, thereby causing increased apoptosis. These findings suggest that restoration of death receptor-mediated apoptotic pathway in tumor cells with concomitant activation of TAMs could effectively restrict tumor growth.
机译：药物难以到达血管的不良血管层是癌症治疗中的限制因素之一。随着旁观者效应（BE）的出现，有可能使细胞从药物暴露的细胞永久性损害到未暴露的细胞。然而，浸润性肿瘤相关巨噬细胞（TAMs）（肿瘤微环境不可或缺的一部分）在进一步强化BE中的作用仍然不清楚。在本研究中，我们评估了丝裂霉素C（MMC）（一种化疗药物）在宫颈癌中诱导BE的作用。通过使用宫颈癌细胞和分化的巨噬细胞，我们证明了MMC通过在两种细胞类型（效应细胞）中上调PPARγ诱导FasL的表达，但未能诱导旁观者杀死宫颈癌细胞。该作用主要是由于宫颈癌细胞中死亡受体的蛋白酶体降解。用蛋白酶体抑制剂MG132预处理宫颈癌细胞，有助于在共培养和条件培养基转移实验中杀死MMC介导的旁观者。与单独使用任何一种药物治疗的小鼠相比，在携带MMC和MG132组合治疗的带有异种移植HeLa肿瘤的NOD / SCID小鼠中，肿瘤的进展明显降低。在TAM中FasL表达增加，并且在这些肿瘤切片中观察到Fas的水平升高，从而导致凋亡增加。这些发现表明，在肿瘤细胞中死亡受体介导的凋亡途径的恢复与TAM的同时活化可以有效地限制肿瘤的生长。

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