Cancer and nutrition: role of amino acids (AA) for the regulation of hepatocellular apoptosis

Mayer, M; Ellinger, Adolf; Karwan, Anneliese; Schulte‐Hermann, Rolf; Bursch, Wilfried

doi:10.1186/1471-2210-7-s2-a64

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“…In addition to the potential role of mitochondria, evidence suggesting the involvement of the mTOR/S6K1 pathway in the induction of cell death upon glucose withdrawal has been reported (Hwang and Lee, 2008). Finally, deprivation of branched chain-amino acids (BCAA), but also of other amino acids (AA)), exerted a pro-apoptotic activity on HCC-1.2 cells; AAdeprivation and TGF-␤1 appear to act additively (Mayer et al, 2007).…”

Section: Autophagy: Response To Metabolic Challenges Link To Nutritimentioning

confidence: 99%

Cell death and autophagy: Cytokines, drugs, and nutritional factors

Bursch¹,

Karwan²,

Mayer³

et al. 2008

Toxicology

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Cells may use multiple pathways to commit suicide. In certain contexts, dying cells generate large amounts of autophagic vacuoles and clear large proportions of their cytoplasm, before they finally die, as exemplified by the treatment of human mammary carcinoma cells with the anti-estrogen tamoxifen (TAM, <= 1 mu M). Protein analysis during autophagic cell death revealed distinct proteins of the nuclear fraction including CST-pi and some proteasomal subunit constituents to be affected during autophagic cell death. Depending on the functional status of caspase-3, MCF-7 cells may switch between autophagic and apoptotic features of cell death [Fazi, B., Bursch, W., Fimia, G.M., Nardacci R., Piacentini, M., Di Sano, F., Piredda. L., 2008. Fenretinide induces autophagic cell death in caspase-defective breast cancer cells. Autophagy 4(4), 435-441]. Furthermore, the self-destruction of MCF-7 cells was found to be completed by phagocytosis of cell residues [Petrovski, G., Zahuczky, G., Katona, K., Vereb, G., Martinet. W., Nemes, Z., Bursch, W., Fesus, L., 2007. Clearance of dying autophagic cells of different origin by professional and non-professional phagocytes. Cell Death Diff. 14 (6),1117-1128]. Autophagy also constitutes a cell's strategy of defense upon cell damage by eliminating damaged bulk proteins/organelles. This biological condition may be exemplified by the treatment of MCF-7 cells with a necrogenic TAM-dose (10 mu M), resulting in the lysis of almost all cells within 24 h. However, a transient (1 h) challenge of MCF-7 cells with the same dose allowed the recovery of cells involving autophagy. Enrichment of chaperones in the insoluble cytoplasmic protein fraction indicated the formation of aggresomes, a potential trigger for autophagy. In a further experimental model HL60 cells were treated with TAM, causing dose-dependent distinct responses: 1-5 mu M TAM, autophagy predominant; 7-9 mu M, apoptosis predominant; 15 mu M, necrosis. These phenomena might be attributed to the degree of cell damage caused by tamoxifen, either by generating ROS, increasing membrane fluidity or forming DNA-adducts. Finally, autophagy constitutes a cell's major adaptive (survival) strategy in response to metabolic challenges such as glucose or amino acid deprivation, or starvation in general. Notably, the role of autophagy appears not to be restricted to nutrient recycling in order to maintain energy supply of cells and to adapt cell(organ) size to given physiological needs. For instance, using a newly established hepatoma cell line HCC-1.2, amino acid and glucose deprivation revealed a pro-apoptotic activity, additive to TGF-beta 1.The proapoptotic action of glucose deprivation was antagonized by 2-deoxyglucose, possibly by stabilizing the mitochondrial membrane involving the action of hexokinase II. These observations suggest that signaling cascades steering autophagy appear to provide links to those regulating cell number. Taken together, our data exemplify that a given cell may flexibly respond to type and degree of (micro)envir...

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Section: Autophagy: Response To Metabolic Challenges Link To Nutritimentioning

confidence: 99%