Autophagy Is Activated by TGF-β and Potentiates TGF-β-Mediated Growth Inhibition in Human Hepatocellular Carcinoma Cells
Autophagy Is Activated by TGF-β and Potentiates TGF-β-Mediated Growth Inhibition in Human Hepatocellular Carcinoma Cells
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DOI：
10.1158/0008-5472.can-08-4401
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发表时间：
2009-12-01
期刊：
影响因子：
11.2
通讯作者：
Miyazono, Kohei
中科院分区：
文献类型：
--
作者：
Kiyono, Kunihiko;Suzuki, Hiroshi I.;Miyazono, Kohei
转化生长因子- β (tgf - β)是一种调节多种细胞生长、分化和凋亡的多功能细胞因子。自噬是正常细胞和癌细胞对环境变化的关键反应，但tgf - β信号和自噬之间的关系尚不清楚。在这里，我们发现tgf - β在人肝癌细胞中激活自噬。tgf - β诱导自噬体的积累和微管相关蛋白I轻链3的转化，提高了长寿命蛋白的降解率。tgf - β增加BECLIN1、ATG5、ATG7和死亡相关蛋白激酶（DAPK） mRNA表达水平。敲低Smad2/3、Smad4或DAPK，或抑制c-Jun nh2末端激酶，可减弱tgf - β诱导的自噬，表明Smad和非Smad途径都参与其中。tgf - β激活自噬早于细胞凋亡（6-12 h和48 h），通过小干扰RNA减少自噬基因减弱tgf - β介导的生长抑制和诱导促凋亡基因Bim和Bmf，提示自噬途径参与tgf - β的生长抑制作用。此外，tgf - β还在一些乳腺癌细胞中诱导自噬，包括MDA-MB-231细胞。这些发现表明tgf - β信号通路在某些人类癌细胞中激活自噬，诱导自噬是tgf - β生物学功能的一个新方面。[癌症研究2009；69 (23): 8844 - 52)
Transforming growth factor-beta (TGF-beta) is a multifunctional cytokine that regulates cell growth, differentiation, and apoptosis of various types of cells. Autophagy is emerging as a critical response of normal and cancer cells to environmental changes, but the relationship between TGF-beta signaling and autophagy has been poorly understood. Here, we showed that TGF-beta activates autophagy in human hepatocellular carcinoma cell tines. TGF-beta induced accumulation of autophagosomes and conversion of microtubule-associated protein I light chain 3 and enhanced the degradation rate of long-lived proteins. TGF-beta increased the mRNA expression levels of BECLIN1, ATG5, ATG7, and death-associated protein kinase (DAPK). Knockdown of Smad2/3, Smad4, or DAPK, or inhibition of c-Jun NH2-terminal kinase, attenuated TGF-beta-induced autophagy, indicating the involvement of both Smad and non-Smad pathway(s). TGF-beta activated autophagy earlier than execution of apoptosis (6-12 versus 48 h), and reduction of autophagy genes by small interfering RNA attenuated TGF-beta-mediated growth inhibition and induction of proapoptotic genes Bim and Bmf, suggesting the contribution of autophagy pathway to the growth-inhibitory effect of TGF-beta. Additionally, TGF-beta also induced autophagy in some mammary carcinoma cells, including MDA-MB-231 cells. These findings show that TGF-beta signaling pathway activates autophagy in certain human cancer cells and that induction of autophagy is a novel aspect of biological functions of TGF-beta. [Cancer Res 2009;69(23):8844-52]