angiogenesis ͉ gastric cancer ͉ molecular targeting therapy ͉ pancreatic cancer

Transforming growth factor-β (TGF-β) 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-β signaling and autophagy has been poorly understood. Here, we showed that TGF-β activates autophagy in human hepatocellular carcinoma cell lines. TGF-β induced accumulation of autophagosomes and conversion of microtubule-associated protein 1 light chain 3 and enhanced the degradation rate of long-lived proteins. TGF-β 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 NH 2 -terminal kinase, attenuated TGF-β-induced autophagy, indicating the involvement of both Smad and non-Smad pathway(s). TGF-β activated autophagy earlier than execution of apoptosis (6-12 versus 48 h), and reduction of autophagy genes by small interfering RNA attenuated TGF-β-mediated growth inhibition and induction of proapoptotic genes Bim and Bmf, suggesting the contribution of autophagy pathway to the growth-inhibitory effect of TGF-β. Additionally, TGF-β also induced autophagy in some mammary carcinoma cells, including MDA-MB-231 cells. These findings show that TGF-β signaling pathway activates autophagy in certain human cancer cells and that induction of autophagy is a novel aspect of biological functions of TGF-β. [Cancer Res 2009;69(23):8844-52]

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