Autophagy is activated by TGF-beta and potentiates TGF-beta-mediated growth inhibition in human hepatocellular carcinoma cells.

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.

• Authors: Kunihiko Kiyono, Hiroshi I Suzuki, Hironori Matsuyama, Yasuyuki Morishita, Akiyoshi Komuro, Mitsunobu R Kano, Koichi Sugimoto, Kohei Miyazono
• Journal: Cancer research (Cancer Res) Vol. 69 Issue 23 Pg. 8844-52 (Dec 01 2009) ISSN: 1538-7445 [Electronic] United States
• PMID: 19903843 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATG5 protein, human
• Adaptor Proteins, Signal Transducing
• Apoptosis Regulatory Proteins
• Autophagy-Related Protein 5
• BCL2L11 protein, human
• BECN1 protein, human
• BMF protein, human
• Bcl-2-Like Protein 11
• Beclin-1
• Membrane Proteins
• Microtubule-Associated Proteins
• Proto-Oncogene Proteins
• Receptors, Transforming Growth Factor beta
• Smad Proteins
• Transforming Growth Factor beta
• JNK Mitogen-Activated Protein Kinases
• ATG7 protein, human
• Autophagy-Related Protein 7
• Ubiquitin-Activating Enzymes

Topics

• Adaptor Proteins, Signal Transducing (biosynthesis, genetics)
• Apoptosis Regulatory Proteins (antagonists & inhibitors, biosynthesis, genetics)
• Autophagy (physiology)
• Autophagy-Related Protein 5
• Autophagy-Related Protein 7
• Bcl-2-Like Protein 11
• Beclin-1
• Breast Neoplasms (genetics, metabolism, pathology)
• Carcinoma, Hepatocellular (genetics, metabolism, pathology)
• Cell Growth Processes (physiology)
• Cell Line, Tumor
• Humans
• JNK Mitogen-Activated Protein Kinases (metabolism)
• Liver Neoplasms (genetics, metabolism, pathology)
• Membrane Proteins (antagonists & inhibitors, biosynthesis, genetics)
• Microtubule-Associated Proteins (antagonists & inhibitors, biosynthesis, genetics)
• Proto-Oncogene Proteins (biosynthesis, genetics)
• Receptors, Transforming Growth Factor beta (metabolism)
• Smad Proteins (metabolism)
• Transfection
• Transforming Growth Factor beta (biosynthesis, genetics, physiology)
• Ubiquitin-Activating Enzymes (antagonists & inhibitors, biosynthesis, genetics)