Identification of LDH-A as a therapeutic target for cancer cell killing via (i) p53/NAD(H)-dependent and (ii) p53 independent pathways

Most cancer cells use aerobic glycolysis to fuel their growth. The enzyme lactate dehydrogenase-A (LDH-A) is key to cancer’s glycolytic phenotype, catalysing the regeneration of nicotinamide adenine dinucleotide (NAD þ ) from reduced nicotinamide adenine dinucleotide (NADH) necessary to sustain glycolysis. As such, LDH-A is a promising target for anticancer therapy. Here we ask if the tumour suppressor p53, a major regulator of cellular metabolism, influences the response of cancer cells to LDH-A suppression. LDH-A knockdown by RNA interference (RNAi) induced cancer cell death in p53 wild-type, mutant and p53-null human cancer cell lines, indicating that endogenous LDH-A promotes cancer cell survival irrespective of cancer cell p53 status. Unexpectedly,however,weuncoveredanovelroleforp53intheregulationofcancercellNADþ anditsreducedformNADH.Thus, LDH-A silencing by RNAi, or its inhibition using a small-molecule inhibitor, resulted in a p53-dependent increase in the cancer cell ratioofNADH:NADþ.Thiseffectwasspecificforp53þ/þ cancercellsandcorrelatedwith(i)reducedactivityofNADþ-dependent deacetylase sirtuin 1 (SIRT1) and (ii) an increase in acetylated p53, a known target of SIRT1 deacetylation activity. In addition, activation of the redox-sensitive anticancer drug EO9 was enhanced selectively in p53 þ / þ cancer cells, attributable to increased activity of NAD(P)H-dependent oxidoreductase NQO1 (NAD(P)H quinone oxidoreductase 1). Suppressing LDH-A increased EO9-inducedDNAdamageinp53þ/þ cancercells,butimportantlyhadnoadditiveeffectinnon-cancercells.Ourresultsidentifya unique strategy by which the NADH/NADþ cellular redox status can be modulated in a cancer-specific, p53-dependent manner and we show that this can impact upon the activity of important NAD(H)-dependent enzymes. To summarise, this work indicates two distinct mechanisms by which suppressing LDH-A could potentially be used to kill cancer cells selectively, (i) through induction of apoptosis, irrespective of cancer cell p53 status and (ii) as a part of a combinatorial approach with redox-sensitive anticancer drugs via a novel p53/NAD(H)-dependent mechanism

Eukaryotic Elongation Factor 2 Kinase Activity Is Required for the Phenotypes of the Rpl24Bst Mouse

John R.P.Knight, Christopher G.Proud, Giovanna Mallucci, Tobiasvon der Haar, C. Mark Smales, Anne E.Willis, Owen J.Sanso

Psychology and aggression

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68264/2/10.1177_002200275900300301.pd

Stubbornness, Power, and Equilibrium Selection in Repeated Games with Multiple Equilibria

Axelord’s [(1970), Conflict of Interest, Markham Publishers, Chicago] index of conflict in 2 ×  2 games with two pure strategy equilibria has the property that a reduction in the cost of holding out corresponds to an increase in conflict. This article takes the opposite view, arguing that if losing becomes less costly, a player is less likely to gamble to win, which means that conflict will be less frequent. This approach leads to a new power index and a new measure of stubbornness, both anchored in strategic reasoning. The win probability defined as power constitutes an equilibrium refinement which differs from Harsanyi and Selten’s [(1988), A General Theory of Equilibrium Selection in Games, MIT Press, Cambridge] refinement. In contrast, Axelrod’s approach focuses on preferences regarding divergences from imaginary outmost rewards that cannot be obtained jointly. The player who is less powerful in an asymmetric one-shot game becomes more powerful in the repeated game, provided he or she values the future sufficiently more than the opponent. This contrasts with the view that repetition induces cooperation, but conforms with the expectation that a more patient player receives a larger share of the pie. Copyright Springer Science+Business Media, LLC 2007conflict, discounting, equilibrium refinement, equilibrium selection, power index, repeated game, stubbornness incentive, C72, D74,