Kindlin-2 links mechano-environment to proline synthesis and tumor growth
Kindlin-2 links mechano-environment to proline synthesis and tumor growth
复制标题
Kindlin-2 将机械环境与脯氨酸合成和肿瘤生长联系起来
DOI：
10.1038/s41467-019-08772-3
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发表时间：
2019-02-19
影响因子：
16.6
通讯作者：
Wu, Chuanyue
中科院分区：
文献类型：
--
作者：
Guo, Ling;Cui, Chunhong;Wu, Chuanyue
细胞代谢受机械环境的影响很大。我们发现，Kindlin-2的一部分定位于线粒体，并与合成脯氨酸的关键酶--吡咯烷-5-羧酸还原酶1(PYCR1)相互作用。细胞外基质(ECM)硬化促进Kindlin-2易位到线粒体并与PYCR1相互作用，导致PYCR1水平升高，进而促进Pro合成和细胞增殖。Kindlin-2的缺失降低了PYCR1的水平，增加了活性氧(ROS)的产生和细胞的凋亡，并取消了ECM僵硬诱导的Pro合成和细胞增殖的增加。在体内，肺腺癌中Kindlin-2和PYCR1的水平均显著升高。去除肺腺癌中的kindlin-2可显著降低体内PYCR1和Pro水平，减轻体内纤维化，从而显著抑制肿瘤生长，降低死亡率。我们的发现揭示了一个机械响应的Kindlin-2-PYCR1复合体，它将机械环境与脯氨酸代谢和信号联系起来，并提出了抑制肿瘤生长的策略。
Cell metabolism is strongly influenced by mechano-environment. We show here that a fraction of kindlin-2 localizes to mitochondria and interacts with pyrroline-5-carboxylate reductase 1 (PYCR1), a key enzyme for proline synthesis. Extracellular matrix (ECM) stiffening promotes kindlin-2 translocation into mitochondria and its interaction with PYCR1, resulting in elevation of PYCR1 level and consequent increase of proline synthesis and cell proliferation. Depletion of kindlin-2 reduces PYCR1 level, increases reactive oxygen species (ROS) production and apoptosis, and abolishes ECM stiffening-induced increase of proline synthesis and cell proliferation. In vivo, both kindlin-2 and PYCR1 levels are markedly increased in lung adenocarcinoma. Ablation of kindlin-2 in lung adenocarcinoma substantially reduces PYCR1 and proline levels, and diminishes fibrosis in vivo, resulting in marked inhibition of tumor growth and reduction of mortality rate. Our findings reveal a mechanoresponsive kindlin-2-PYCR1 complex that links mechano-environment to proline metabolism and signaling, and suggest a strategy to inhibit tumor growth.