Autophagy Inhibition Induces the Secretion of Macrophage Migration Inhibitory Factor (MIF) with Autocrine and Paracrine Effects on the Promotion of Malignancy in Breast Cancer
Autophagy Inhibition Induces the Secretion of Macrophage Migration Inhibitory Factor (MIF) with Autocrine and Paracrine Effects on the Promotion of Malignancy in Breast Cancer
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DOI：
10.3390/biology9010020
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发表时间：
2020-01-01
期刊：
影响因子：
4.2
通讯作者：
Maycotte, Paola
中科院分区：
文献类型：
--
作者：
Cotzomi-Ortega, Israel;Rosas-Cruz, Arely;Maycotte, Paola
乳腺癌是世界上妇女癌症相关死亡的主要原因。由于自噬是一种已知的癌细胞生存途径，目前正在临床试验中探索其抑制作用，以治疗几种类型的恶性肿瘤。在乳腺癌中，自噬已被证明是三阴性亚型（TNBC）癌细胞存活所必需的，TNBC是乳腺癌中预后最差的亚型，目前的治疗选择有限。自噬也参与了蛋白质分泌的调节，对于这项工作来说，重要的是，自噬的抑制可以促进不同细胞类型的促炎细胞因子的分泌。我们发现抑制TNBC细胞系的自噬诱导巨噬细胞迁移抑制因子（MIF）的分泌，巨噬细胞迁移抑制因子是一种参与乳腺癌侵袭和免疫调节的促肿瘤细胞因子。MIF的分泌依赖于自噬抑制诱导的活性氧（ROS）的增加。重要的是，自噬缺陷细胞分泌的MIF增加了未使用自噬抑制剂处理的细胞的迁移，这表明癌细胞的自噬抑制通过分泌因子的释放促进了邻近细胞的恶性肿瘤，应该评估一种组合方法用于癌症治疗。
Breast cancer is the main cause of cancer-related death in women in the world. Because autophagy is a known survival pathway for cancer cells, its inhibition is currently being explored in clinical trials for treating several types of malignancies. In breast cancer, autophagy has been shown to be necessary for the survival of cancer cells from the triple negative subtype (TNBC), which has the worst prognosis among breast cancers and currently has limited therapeutic options. Autophagy has also been involved in the regulation of protein secretion and, of importance for this work, the inhibition of autophagy is known to promote the secretion of proinflammatory cytokines from distinct cell types. We found that the inhibition of autophagy in TNBC cell lines induced the secretion of the macrophage migration inhibitory factor (MIF), a pro-tumorigenic cytokine involved in breast cancer invasion and immunomodulation. MIF secretion was dependent on an increase in reactive oxygen species (ROS) induced by the inhibition of autophagy. Importantly, MIF secreted from autophagy-deficient cells increased the migration of cells not treated with autophagy inhibitors, indicating that autophagy inhibition in cancer cells promoted malignancy in neighboring cells through the release of secreted factors, and that a combinatorial approach should be evaluated for cancer therapy.