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.
Highlights
Autophagy is an evolutionally conserved lysosomal degradation pathway in which the cell self-digests its proteins and organelles and maintains macromolecular synthesis and ATP production [1]
Because many lines of evidence suggest a link between autophagy and cell death including apoptosis [5], we first examined the effect of Transforming growth factor-β (TGF-β) on autophagy in HuH7 human hepatocellular carcinoma cells, which undergo apoptosis and cell cycle arrest by TGF-β [27]
We showed that TGF-β induced autophagy in certain hepatocellular carcinoma and mammary carcinoma cell lines
Summary
Autophagy is an evolutionally conserved lysosomal degradation pathway in which the cell self-digests its proteins and organelles and maintains macromolecular synthesis and ATP production [1]. Autophagy enables the cell to survive under various stress conditions including nutrient deprivation, growth factor depletion, and hypoxia [2,3,4,5]. Autophagy plays an important role in the elimination of misfolded protein aggregates, invading microorganisms, and damaged organelles [6, 7]. The membrane wraps some cytoplasmic contents and transforms into the autophagosome, which fuses with the lysosome and degrades its contents [2, 8, 9]. BECLIN1 is a component of the class III phosphoinositide 3-kinase complex and plays an important role in autophagy regulation. Depletion of cellular energy and reduced amino acid levels stimulate autophagy through the inhibition of mammalian target of rapamycin (mTOR; 1, 9)
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