Suppression of autophagy by FIP200 deletion inhibits mammary tumorigenesis
Suppression of autophagy by FIP200 deletion inhibits mammary tumorigenesis
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DOI：
10.1101/gad.2051011
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发表时间：
2011-07-15
影响因子：
10.5
通讯作者：
Guan, Jun-Lin
中科院分区：
文献类型：
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作者：
Wei, Huijun;Wei, Shuang;Guan, Jun-Lin
自噬是溶酶体中细胞内蛋白质和细胞器大量降解的保守细胞过程。与使用小鼠模型和培养细胞对 beclin1 进行的优雅研究相比，这些研究显示了自噬的肿瘤抑制功能，敲除各种组织中的其他必需自噬蛋白，如 ATG5、ATG7 或 FIP200（200 kDa 的 FAK 家族相互作用蛋白）并不会导致体内恶性肿瘤的发展。在此，我们报告在由 PyMT 癌基因驱动的小鼠乳腺癌模型中，通过 FIP200 消融抑制自噬可抑制乳腺肿瘤的发生和进展。 FIP200的缺失导致多种自噬缺陷，包括泛素化蛋白聚集体和p62/SQSTM1的积累、LC3转换缺陷以及肿瘤细胞中形态异常的线粒体数量增加。 FIP200缺失并不影响乳腺肿瘤细胞或Ras转化的小鼠胚胎成纤维细胞(MEF)的凋亡，但显着降低了它们在两个系统中的增殖。我们还观察到 FIP200 缺失的乳腺肿瘤细胞和转化的 MEF 中糖酵解和细胞周期蛋白 D1 表达减少。此外，基因分析研究显示，FIP200条件敲除小鼠的早期肿瘤中干扰素（IFN）反应基因的表达显着升高，同时伴随着肿瘤微环境中效应T细胞的浸润增加，这是由FIP200无效肿瘤细胞中包括CXCL10在内的趋化因子产生增加所引发的。总之，这些数据为自噬在致癌基因诱导的体内肿瘤中的促肿瘤发生作用提供了强有力的证据，并表明 FIP200 作为癌症治疗的潜在靶点。
Autophagy is a conserved cellular process for bulk degradation of intracellular protein and organelles in lysosomes. In contrast to elegant studies of beclin1 using mouse models and cultured cells demonstrating a tumor suppression function for autophagy, knockout of other essential autophagy proteins such as ATG5, ATG7, or FIP200 (FAK family-interacting protein of 200 kDa) in various tissues did not lead to malignant tumor development in vivo. Here, we report that inhibition of autophagy by FIP200 ablation suppresses mammary tumor initiation and progression in a mouse model of breast cancer driven by the PyMT oncogene. Deletion of FIP200 resulted in multiple autophagy defects including accumulation of ubiquitinated protein aggregates and p62/SQSTM1, deficient LC3 conversion, and increased number of mitochondria with abnormal morphology in tumor cells. FIP200 deletion did not affect apoptosis of mammary tumor cells or Ras-transformed mouse embryonic fibroblasts (MEFs), but significantly reduced their proliferation in both systems. We also observed a reduced glycolysis and cyclin D1 expression in FIP200-null mammary tumor cells and transformed MEFs. In addition, gene profiling studies revealed significantly elevated expression of interferon (IFN)-responsive genes in the early tumors of FIP200 conditional knockout mice, which was accompanied by increased infiltration of effector T cells in the tumor microenvironment triggered by an increased production of chemokines including CXCL10 in FIP200-null tumor cells. Together, these data provide strong evidence for a protumorigenesis role of autophagy in oncogene-induced tumors in vivo and suggest FIP200 as a potential target for cancer therapy.