BACKGROUND/AIMS: The AKT survival pathway is involved in a wide variety of human cancers. We investigated the implication of this pathway in hereditary tyrosinemia type 1 (HT1), a metabolic disease exhibiting hepatocellular carcinoma (HCC), despite treatment with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexadione (NTBC) which prevents liver damage. HT1 is an autosomal recessive disorder caused by accumulation of toxic metabolites due to a deficiency in fumarylacetoacetate hydrolase (FAH), the last enzyme in the catabolism of tyrosine. METHODS: NTBC withdrawal in the murine fah(-/-) knockout model was used to analyze in vivo the correlation between pathophysiological, biochemical and histological features consistent with hepatocarcinogenesis and activation of the AKT survival pathway. RESULTS: The HT1 stress initiated by NTBC discontinuation causes a progressive increase of liver and kidney pathophysiology. A stable activation of the AKT survival pathway is observed in the liver but not in kidneys of fah(-/-) mice. Hepatic survival is reinforced by inhibition of mitochondrial-mediated apoptosis through inactivation of Bad and induction of BCl-X(L) and BCl-2. CONCLUSIONS: The chronic stress induced by liver disease in HT1 activates the AKT survival signal and inhibits intrinsic apoptosis to confer cell death resistance in vivo and favor hepatocarcinogenesis.
BACKGROUND/AIMS: The AKT survival pathway is involved in a wide variety of humancancers. We investigated the implication of this pathway in hereditary tyrosinemia type 1 (HT1), a metabolic disease exhibiting hepatocellular carcinoma (HCC), despite treatment with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexadione (NTBC) which prevents liver damage. HT1 is an autosomal recessive disorder caused by accumulation of toxic metabolites due to a deficiency in fumarylacetoacetate hydrolase (FAH), the last enzyme in the catabolism of tyrosine. METHODS:NTBC withdrawal in the murinefah(-/-) knockout model was used to analyze in vivo the correlation between pathophysiological, biochemical and histological features consistent with hepatocarcinogenesis and activation of the AKT survival pathway. RESULTS: The HT1 stress initiated by NTBC discontinuation causes a progressive increase of liver and kidney pathophysiology. A stable activation of the AKT survival pathway is observed in the liver but not in kidneys of fah(-/-) mice. Hepatic survival is reinforced by inhibition of mitochondrial-mediated apoptosis through inactivation of Bad and induction of BCl-X(L) and BCl-2. CONCLUSIONS: The chronic stress induced by liver disease in HT1 activates the AKT survival signal and inhibits intrinsic apoptosis to confer cell death resistance in vivo and favor hepatocarcinogenesis.
Authors: Sebene Mayorandan; Uta Meyer; Gülden Gokcay; Nuria Garcia Segarra; Hélène Ogier de Baulny; Francjan van Spronsen; Jiri Zeman; Corinne de Laet; Ute Spiekerkoetter; Eva Thimm; Arianna Maiorana; Carlo Dionisi-Vici; Dorothea Moeslinger; Michaela Brunner-Krainz; Amelie Sophia Lotz-Havla; José Angel Cocho de Juan; Maria Luz Couce Pico; René Santer; Sabine Scholl-Bürgi; Hanna Mandel; Yngve Thomas Bliksrud; Peter Freisinger; Luis Jose Aldamiz-Echevarria; Michel Hochuli; Matthias Gautschi; Jessica Endig; Jens Jordan; Patrick McKiernan; Stefanie Ernst; Susanne Morlot; Arndt Vogel; Johannes Sander; Anibh Martin Das Journal: Orphanet J Rare Dis Date: 2014-08-01 Impact factor: 4.123