Abstract
Tumor cells trends to express high level of pyruvate kinase M2 (PKM2). The inhibition of PKM2 activity is needed for antioxidant response by diverting glucose flux into the pentose phosphate pathway and thus generating sufficient reducing potential. Here we report that PKM2 is succinylated at lysine 498 (K498) and succinylation increases its activity. SIRT5 binds to, desuccinylates and inhibits PKM2 activity. Increased level of reactive oxygen species (ROS) decreases both the succinylation and activity of PKM2 by increasing its binding to SIRT5. Substitution of endogenous PKM2 with a succinylation mimetic mutant K498E decreases cellular NADPH production and inhibits cell proliferation and tumor growth. Moreover, inhibition of SIRT5 suppresses tumor cell proliferation through desuccinylation of PKM2 K498. These results reveal a new mechanism of PKM2 modification, a new function of SIRT5 in response to oxidative stress which stimulates cell proliferation and tumor growth, and also a potential target for clinical cancer research.
Highlights
In contrast to normal proliferating cells, tumor cells have to survive in environments with varying oxygen and nutrient supplies [1, 2]
A systematic study of mammalian succinylome identified 2,565 succinylation sites on 779 proteins [16], including pyruvate kinase M2 (PKM2). 7 putative succinylation sites of PKM2 was identified by mass spectroscopy and among these sites, only K498 succinylation level of PKM2 increased for 2.6 fold in SIRT5 knockout mice by absolute stoichiometry [16], indicating K498 maybe the major succinylation site of PKM2
We determined the binding of PKM2 to SIRT5, and found that both exogenous and endogenous PKM2 binds to SIRT5 in vitro (Supplementary Figure 1A and 1C)
Summary
In contrast to normal proliferating cells, tumor cells have to survive in environments with varying oxygen and nutrient supplies [1, 2]. These circumstances make special demands upon the metabolism of tumor cells [3, 4]. An important molecular feature of tumor metabolism is the expression of glycolysis enzyme pyruvate kinase isoform M2 (PKM2) [5, 6], which catalyzes the transfer of phosphate from phosphoenolpyruvate (PEP) to ADP, resulting in the formation of pyruvate and ATP. Inhibition of PKM2 accumulates glycolytic intermediates and promotes macromolecular biosynthesis and tumor growth [7,8,9]. The activity of PKM2 can be regulated by several post-translational modification: phosphorylation [10], acetylation [11] and oxidation [12], all of which are very important for tumor growth
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