Phan Trinh T T, Lin Yu-Chun, Chou Yu-Ting, Wu Chien-Wei, Lin Lih-Yuan
Institute of Molecular and Cellular Biology, College of Life Science, National Tsing Hua University, Hsinchu, 300044, Taiwan ROC.
Institute of Molecular Medicine, College of Life Science, National Tsing Hua University, Hsinchu, 300044, Taiwan ROC.
Oncogenesis. 2022 May 19;11(1):26. doi: 10.1038/s41389-022-00401-x.
Tumor suppressor p53 plays a central role in preventing tumorigenesis. Here, we unravel how p53 modulates mitochondrial dynamics to restrain the metastatic properties of cancer cells. p53 inhibits the mammalian target of rapamycin complex 1 (mTORC1) signaling to attenuate the protein level of mitochondrial fission process 1 (MTFP1), which fosters the pro-fission dynamin-related protein 1 (Drp1) phosphorylation. This regulatory mechanism allows p53 to restrict cell migration and invasion governed by Drp1-mediated mitochondrial fission. Downregulating p53 expression or elevating the molecular signature of mitochondrial fission correlates with aggressive tumor phenotypes and poor prognosis in cancer patients. Upon p53 loss, exaggerated mitochondrial fragmentation stimulates the activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling resulting in epithelial-to-mesenchymal transition (EMT)-like changes in cell morphology, accompanied by accelerated matrix metalloproteinase 9 (MMP9) expression and invasive cell migration. Notably, blocking the activation of mTORC1/MTFP1/Drp1/ERK1/2 axis completely abolishes the p53 deficiency-driven cellular morphological switch, MMP9 expression, and cancer cell dissemination. Our findings unveil a hitherto unrecognized mitochondria-dependent molecular mechanism underlying the metastatic phenotypes of p53-compromised cancers.
肿瘤抑制因子p53在预防肿瘤发生过程中发挥着核心作用。在此，我们揭示了p53如何调节线粒体动力学以抑制癌细胞的转移特性。p53抑制雷帕霉素复合物1（mTORC1）信号通路的哺乳动物靶点，以降低线粒体裂变过程1（MTFP1）的蛋白质水平，MTFP1可促进促裂变动力相关蛋白1（Drp1）的磷酸化。这种调节机制使p53能够限制由Drp1介导的线粒体裂变所控制的细胞迁移和侵袭。下调p53表达或提高线粒体裂变的分子特征与癌症患者侵袭性肿瘤表型和不良预后相关。p53缺失后，过度的线粒体碎片化会刺激细胞外信号调节激酶1/2（ERK1/2）信号通路的激活，导致细胞形态发生上皮-间质转化（EMT）样变化，同时伴随着基质金属蛋白酶9（MMP9）表达加速和细胞侵袭性迁移。值得注意的是，阻断mTORC1/MTFP1/Drp1/ERK1/2轴的激活可完全消除p53缺陷驱动的细胞形态转变、MMP9表达和癌细胞扩散。我们的研究结果揭示了一种迄今未被认识的线粒体依赖性分子机制，该机制是p53功能受损癌症转移表型的基础。
