Seminar: Prof. Patrick Pollard

Oncometabolites: linking altered metabolism with cancer?

9 January 2014 00:00 hrs.
Figdor Lecture Theatre, 8th floor RIMLS Building, Geert Grooteplein 26-28, route 289
Oncometabolites: linking altered metabolism with cancer?

Prof. Patrick Pollard, Institute of Genetics and Molecular Medicine, University of Edinburgh, UK


Prof. Peter Deen, department of Physiology, Radboudumc

09-01-2014 00:00:00Europe/AmsterdamOncometabolites: linking altered metabolism with cancer? Figdor Lecture Theatre, 8th floor RIMLS Building, Geert Grooteplein 26-28, route

Remarks / more information:


MMD Course: Oxygen in health and disease

Pollard , PatrickCancer associated mutations have been identified in the metabolic genes Succinate dehydrogenase (SDH), Fumarate hydratase (FH) and Isocitrate dehydrogenase (IDH), advancing and challenging our understanding of cellular function and disease mechanisms and providing direct links between dysregulated metabolism and cancer. Some striking parallels exist in the cellular consequences of the genetic mutations within this triad of cancer syndromes, including accumulation of oncometabolites and competitive inhibition of 2-oxoglutarate-(2OG)-dependent dioxygenases, particularly hypoxia-inducible factor prolyl hydroxylases (HIF-PHDs), JmjC domain-containing histone demethylases (part of the JMJD family) and the TET (ten-eleven translocation) family of 5methyl Cytosine (5mC) DNA hydroxylases. These lead to activation of HIF-dependent oncogenic pathways, inhibition of histone and DNA demethylation and hydroxylation of 5mC. Mutations in FH, resulting in loss of enzyme activity, predispose affected individuals to a rare cancer, hereditary leiomyomatosis and renal cell cancer (HLRCC), characterized by benign smooth muscle cutaneous and uterine tumours (leiomyomata) and an aggressive form of collecting duct and Type 2 papillary renal cancer. Interestingly, loss of FH activity results in the accumulation of high levels of fumarate that can lead to the non-enzymatic modification of cysteine residues in multiple proteins (succination) and in some cases to their disrupted function. Here we consider that the study of rare diseases such as HLRCC, combining analyses of human tumours and cell lines with in vitro and in vivo murine models has provided novel insights into cancer biology associated with dysregulated metabolism and represents a useful paradigm for cancer research.

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