Abstract# 5302: Fumarate hydratase deficiency induces glycolytic addiction and a HIF1-\# 945; amplification loop stabilized by glucose-dependent generation of reactive oxygen species

摘要: Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) is an inherited cancer syndrome linked to biallelic inactivation of the gene encoding the tricarboxylic acid cycle enzyme fumarate hydratase (FH). Individuals with HLRCC are at risk to develop cutaneous and uterine leiomyomas and an aggressive form of kidney cancer. Pseudohypoxic drive - the aberrant activation of cellular hypoxia response pathways despite normal oxygen tension - is considered to be a likely mechanism underlying the etiology of this tumor. Pseudohypoxia requires the oxygen-independent stabilization of the alpha subunit of hypoxia-inducible transcription factor (HIF-1\#945;). Under normoxic conditions, proline hydroxylation of HIF-1\#945; permits VHL recognition and subsequent targeting for proteasomal degradation. Here we demonstrate that inactivating mutations of FH in an HLRCC-derived cell line result in glucose-mediated …