Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
Autophagy. 2010 Jul;6(5):645-7. doi: 10.4161/auto.6.5.12046. Epub 2010 Jul 1.
Transforming growth factor-β (TGF-β) has broad impacts on an array of diverse cellular functions including cell growth, differentiation, adhesion, migration, and apoptosis. Perturbations of the TGF-β signaling pathways are involved in progression of various tumors. Autophagy is a pivotal response of normal and cancer cells to environmental stresses and is induced by various stimuli. Otherwise, autophagy has an intrinsic function in tumor suppression. Recently, we demonstrated that TGF-β induces autophagy in hepatocellular carcinoma cells and mammary carcinoma cells. Autophagy activation by TGF-β is mediated through the Smad and JNK pathways. We show that siRNA-mediated knockdown of autophagy genes suppresses the growth inhibitory function of TGF-β and that autophagy activation potentiates TGF-β-mediated induction of proapoptotic genes, Bim and Bmf, in hepatoma cells. In this context, the autophagy pathway might contribute to the growth inhibitory effect of TGF-β, in conjunction with other anti-proliferative pathways downstream of TGF-β signaling. The context and manner by which the TGF-β signaling pathway regulates autophagy have implications for a better understanding of pathological and bidirectional roles of TGF-β signaling pathways in tumorigenesis.
转化生长因子-β（TGF-β）对多种细胞功能具有广泛的影响，包括细胞生长、分化、黏附、迁移和凋亡。TGF-β信号通路的失调与多种肿瘤的进展有关。自噬是正常细胞和癌细胞对环境应激的关键反应，可被多种刺激诱导。此外，自噬在肿瘤抑制中具有内在功能。最近，我们证明 TGF-β可诱导肝癌细胞和乳腺癌细胞发生自噬。TGF-β 诱导的自噬是通过 Smad 和 JNK 通路介导的。我们表明，siRNA 介导的自噬基因敲低可抑制 TGF-β 的生长抑制功能，并且自噬的激活可增强 TGF-β 介导的促凋亡基因 Bim 和 Bmf 在肝癌细胞中的诱导。在这种情况下，自噬途径可能有助于 TGF-β 的生长抑制作用，与 TGF-β 信号转导下游的其他抗增殖途径协同作用。TGF-β 信号通路调节自噬的背景和方式，对于更好地理解 TGF-β 信号通路在肿瘤发生中的病理性和双向作用具有重要意义。
