Abstract
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 lines. TGF-beta induced accumulation of autophagosomes and conversion of microtubule-associated protein 1 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 NH(2)-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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / biosynthesis
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Adaptor Proteins, Signal Transducing / genetics
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Apoptosis Regulatory Proteins / antagonists & inhibitors
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Apoptosis Regulatory Proteins / biosynthesis
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Apoptosis Regulatory Proteins / genetics
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Autophagy / physiology*
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Autophagy-Related Protein 5
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Autophagy-Related Protein 7
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Bcl-2-Like Protein 11
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Beclin-1
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology
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Carcinoma, Hepatocellular / genetics
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Carcinoma, Hepatocellular / metabolism
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Carcinoma, Hepatocellular / pathology*
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Cell Growth Processes / physiology
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Cell Line, Tumor
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Humans
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JNK Mitogen-Activated Protein Kinases / metabolism
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Liver Neoplasms / genetics
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Liver Neoplasms / metabolism
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Liver Neoplasms / pathology*
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Membrane Proteins / antagonists & inhibitors
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Membrane Proteins / biosynthesis
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Membrane Proteins / genetics
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Microtubule-Associated Proteins / antagonists & inhibitors
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Microtubule-Associated Proteins / biosynthesis
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Microtubule-Associated Proteins / genetics
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Proto-Oncogene Proteins / biosynthesis
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Proto-Oncogene Proteins / genetics
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Receptors, Transforming Growth Factor beta / metabolism
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Smad Proteins / metabolism
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Transfection
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Transforming Growth Factor beta / biosynthesis
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Transforming Growth Factor beta / genetics
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Transforming Growth Factor beta / physiology*
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Ubiquitin-Activating Enzymes / antagonists & inhibitors
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Ubiquitin-Activating Enzymes / biosynthesis
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Ubiquitin-Activating Enzymes / genetics
Substances
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ATG5 protein, human
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Adaptor Proteins, Signal Transducing
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Apoptosis Regulatory Proteins
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Autophagy-Related Protein 5
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BCL2L11 protein, human
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BECN1 protein, human
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BMF protein, human
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Bcl-2-Like Protein 11
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Beclin-1
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Membrane Proteins
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Microtubule-Associated Proteins
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Proto-Oncogene Proteins
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Receptors, Transforming Growth Factor beta
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Smad Proteins
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Transforming Growth Factor beta
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JNK Mitogen-Activated Protein Kinases
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ATG7 protein, human
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Autophagy-Related Protein 7
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Ubiquitin-Activating Enzymes