Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, USA.
Genes Dev. 2011 Jul 15;25(14):1510-27. doi: 10.1101/gad.2051011.
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.
自噬是一种细胞内蛋白质和细胞器在溶酶体中批量降解的保守过程。与使用小鼠模型和培养细胞对 beclin1 进行的精致研究形成对比的是，其他必需的自噬蛋白（如 ATG5、ATG7 或 FIP200（200 kDa 的 FAK 家族相互作用蛋白））在各种组织中的敲除并没有导致体内恶性肿瘤的发展。在这里，我们报告了 FIP200 缺失通过抑制自噬来抑制由 PyMT 癌基因驱动的乳腺癌小鼠模型中的乳腺肿瘤起始和进展。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 转化不足以及肿瘤细胞中线粒体形态异常的数量增加。FIP200 缺失不影响乳腺肿瘤细胞或 Ras 转化的小鼠胚胎成纤维细胞（MEFs）的细胞凋亡，但在这两种系统中均显著降低了它们的增殖。我们还观察到 FIP200 缺失的乳腺肿瘤细胞和转化的 MEFs 中的糖酵解和 cyclin D1 表达减少。此外，基因谱研究显示，FIP200 条件性敲除小鼠的早期肿瘤中干扰素（IFN）反应基因的表达显著上调，伴随着趋化因子（包括 CXCL10）在 FIP200 缺失肿瘤细胞中的增加产生，从而导致肿瘤微环境中效应 T 细胞的浸润增加。总之，这些数据为自噬在体内致癌基因诱导的肿瘤中的促肿瘤发生作用提供了有力证据，并表明 FIP200 是癌症治疗的潜在靶点。
