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SUMMARY:Metabolism and cancer: why should we care? - Professor Eyal Gottli
 eb\, University of Glasgow
DTSTART:20121121T150000Z
DTEND:20121121T160000Z
UID:TALK40759@talks.cam.ac.uk
CONTACT:Penny Peck
DESCRIPTION:In order to engage in fast replicative division\, a cancer cel
 l must duplicate its genome\, synthesise proteins and lipids\, and assembl
 e these components to form daughter cells. These activities require increa
 sed uptake of nutrients to be used as biosynthetic precursors and an energ
 y source. However\, rapid tumour growth surpasses the required blood suppl
 y and exposes cancer cells to extreme conditions of metabolic deficit and 
 stress. Therefore\, cancer cells undergo many metabolic changes (collectiv
 ely known as ‘metabolic transformation’) that support their growth and
  survival. The extent to which metabolism plays a role in tumorigenesis ca
 nnot be overstated and drugs that selectively target these processes are l
 ikely to at least delay\, if not halt tumour progression. Our work utilize
 s analytical chemistry and system biology approaches to study metabolic tr
 ansformation. These technologies are not only important for understanding 
 the basic biochemistry of cancer cells but they can inform us on future cl
 inical management of cancer and may lead to new therapeutic approaches to 
 target cancer-specific metabolic pathways.\n\nWe investigated cancer cells
  in which metabolic transformation is mediated by genetic alterations. The
 se include cells which are deficient in one of the two mitochondrial tumou
 r suppressor genes\, fumarate hydratase (FH) or succinate dehydrogenase (S
 DH) or cells that overexpress the glycolytic enzyme pyruvate kinase (PK) M
 2 isoform (PKM2). We identified several metabolic pathways which are speci
 fic and crucial for the survival of FH-deficient cells. These include the 
 heme biosynthesis and degradation pathway as well as mechanisms of allevia
 ting TCA cycle carbon stress. \n\nIn addition to high glucose consumption 
 and lactate production\, cancer cells are highly dependent on de novo bios
 ynthesis of serine and glycine from glucose. PKM2\, is a highly-regulated 
 PK isoform which catalyses the last step of glycolysis and has recently em
 erged as a potential regulator of these metabolic phenotypes. However\, th
 e mechanisms by which PKM2 coordinates high energy requirements with high 
 anabolic activities\, and supports cancer cell proliferation\, are still n
 ot completely understood. We identified a novel rheostat-like mechanistic 
 relationship between PKM2 activity and serine biosynthesis. We showed that
  serine can bind to and activate PKM2 and that following serine deprivatio
 n\, PKM2 activity in cells is reduced. This reduction in PKM2 activity shi
 fts cells to a fuel-efficient mode where more pyruvate is diverted to the 
 mitochondria and more glucose derived carbon is channelled into serine bio
 synthesis to support cell proliferation.
LOCATION:Sackler Lecture Theatre (Level 7) Wellcome Trust/MRC Building\, A
 ddenbrooke's Site
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