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

Kunihiko Kiyono, Hiroshi I. Suzuki, Hironori Matsuyama, Yasuyuki Morishita, Akiyoshi Komuro, Mitsunobu R. Kano, Koichi Sugimoto, Kohei Miyazono

Research output: Contribution to journalArticle

169 Citations (Scopus)

Abstract

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 NH2-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.

Original languageEnglish
Pages (from-to)8844-8852
Number of pages9
JournalCancer Research
Volume69
Issue number23
DOIs
Publication statusPublished - Dec 1 2009

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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