Cells lacking fumarase are protected from apoptosis through a HIF independent, AMPK dependent mechanism

Author: M. F. Di Renzo
Submitted: Thursday 10th of February 2011 09:29:25 AM
Submitted by: egf
Language: English
Content type: Learning resource
Educational levels: expert, qc3

Abstract

Germline mutations in the Fumarate Hydratase (FH, also known as fumarase) predispose to Hereditary Leiomyomatosis and Renal Cell Carcinoma (HLRCC), a tumor syndrome in which mutation carriers are at risk for developing cutaneous and uterine leiomyomas and an aggressive form of kidney cancer. Fumarate Hydratase gene encodes subunits of an enzyme that catalyses the conversion of fumarate to malate, as part of the tricarboxylic acid cycle in the mitochondrial matrix. FH dysfunction leads to stabilization of the hypoxia inducible transcription factor (HIF) in a normoxic environment. Most of the biological properties and metabolic characteristics of HLRCC tumors could be ascribed to HIF stabilization. Among the genes likely involved in kidney cancer development, we considered MET, as its activating mutations predispose to inherited papillary type 1 renal cell carcinoma (HPRCC) and MET over-expression has been described in most human kidney cancers. Using mouse embryo fibroblasts (MEFs) to model transformation we found that fh knock down results in increased expression of the met oncogene- encoded tyrosine kinase receptor, through hif stabilization, and that Met cooperated with a weakly oncogenic ras in making MEFs transformed and tumorigenic, in the in vitro and in vivo assays. In conclusion, these data suggested that progression of tumors where FH is lost might be boosted by activation of the MET oncogene, which is able to drive cell-autonomous tumor progression and is a strong candidate for targeted therapy. However, data did not explain how a Krebs cycle defect might confer a selective advantage to somatic cells. We found that knocking down FH activity in human renal cells made these cells protected from apoptosis. Accordingly, FH minus human fibroblasts are protected. In FH defective cells, both HIF-1α and HIF-2α accumulated, but were dispensable for apoptosis protection. Conversely, BAD was necessary and was constitutively phosphorylated, i.e. inactivated. A survey of kinases revealed that AKT and AMPK were activated by apoptotic stimuli, but only AMPK regulated BAD phosphorylation and cell protection from apoptosis. These findings uncovered an unexpected activity of AMPK that might contribute to uphold rather than suppress early steps of tumorigenesis by promoting cell survival. The AMP-activated protein kinase (AMPK) senses metabolic stress and integrates energy homeostasis, cell survival and proliferation. In tumor cells, AMPK inactivation allows continued 18 growth under conditions of energy depletion. Therefore, AMPK activation is likely to be of therapeutic value to suppress tumor growth and it is feasible, as pharmacological activators, such as metformin and thiazolidinediones, are already approved for the treatment of diabetes. For their effects on tumor growth and metabolism, these compounds are undergoing clinical trials in human tumors. However, we show that, by mediating BAD phosphorylation, AMPK protects some cells from apoptosis and that, therefore, AMPK therapeutic activation might be not only ineffective, but even harmful in tumors with specific mutation background.

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abstract Fumarase_HIF_and_AMPK_in_apoptosis_and_cancer_DiRenzo_5118.ppt

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M. F. Di Renzo. Cells lacking fumarase are protected from apoptosis through a HIF independent, AMPK dependent mechanism. EUROGENE portal. February 2011. online: http://eurogene.open.ac.uk/content/cells-lacking-fumarase-are-protected-apoptosis-through-hif-independent-ampk-dependent-mechan

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