Inhibition of pyruvate kinase M2 by reactive oxygen species contributes to cellular antioxidant responses

By D. Anastasiou, G. Poulogiannis, J. Asara, M. Boxer, Jian-Kang Jiang, M. Shen, G. Bellinger, Atsuo T. Sasaki, Jason W. Locasale, D. Auld and 3 more. Science, 2011

1,168 citations recorded by the source corpus.

The glycolytic metabolism of cancers differs from normal tissues, allowing tumor cells to survive under oxidative stress. Control of intracellular reactive oxygen species (ROS) concentrations is critical for cancer cell survival. We show that, in human lung cancer cells, acute increases in intracellular concentrations of ROS caused inhibition of the glycolytic enzyme pyruvate kinase M2 (PKM2) through oxidation of Cys358. This inhibition of PKM2 is required to divert glucose flux into the pentose phosphate pathway and thereby generate sufficient reducing potential for detoxification of ROS. Lung cancer cells in which endogenous PKM2 was replaced with the Cys358 to Ser358 oxidation-resistant mutant exhibited increased sensitivity to oxidative stress and impaired tumor formation in a xenograft model. Besides promoting metabolic changes required for proliferation, the regulatory properties of PKM2 may confer an additional advantage to cancer cells by allowing them to withstand oxidative stress.

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Citations in the corpus

Mitochondrial reactive oxygen species and cancer (2014, background): “In contrast to its constitutively active splice isoform PKM1, PKM2 is preferentially expressed in cancer cells and is unique due to its ability to be inhibited by a variety of stimuli [65,66].”
The effects of heavy metals on human metabolism (2019, background): “Hexokinase and pyruvate kinase are known to be inactivated by oxidative stress (Anastasiou et al. 2011).”
ROS homeostasis and metabolism: a dangerous liason in cancer cells (2016, background): “mingly paradoxical, this pro-oxidant shift can promote tumor growth by inducing DNA damage and genomic instability,(2) which then activate an inflammatory response,(3) stabilizing the hypoxia inducible factor-1(4) and thus reprogramming metabolism.(5,6) Due to the selective pressure induced by”
NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential (2020, background): “In cancer cells, increased ROS will oxidize the specific isoform of pyruvate kinase (PKM2), diverting glucose flux towards the PPP and generation of NADPH for GSH recycling.(96,375,376) Similarly, nutrition stress or oxidative stress induces the expression of enzymes, including NAMPT, ME1 and NNT, w”
Anoikis molecular pathways and its role in cancer progression. (2013, background): “In the presence of ROS PK-M2 is converted in a fully inactive form, behaving as a bottleneck for glycolysis and promoting NADPH synthesis through PPP, contributing to decrease ROS levels and leading to anoikis resistance [3].”
Reprogramming of glucose, fatty acid and amino acid metabolism for cancer progression (2015, background): “In addition, some metabolic enzymes in the glycolysis pathway, such as HK2, PFK1, and PKM2, also impact the oxidative or nonoxidative branch of PPP by balancing glycolytic and PPP flux [62–64].”
HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations. (2013, unknown): “First and foremost, PKM2 functions as a pyruvate kinase in glycolysis (Figure 3) but, in contrast to PKM1, its activity is regulated by allosteric interactions with phosphopeptides (67) and intermediary metabolites (68, 69) as well as by phosphorylation, acetylation, and oxidation (70–72).”
T cell metabolism drives immunity (2015, background): “2; Vander Heiden et al., 2009; Anastasiou et al., 2011; Macintyre and Rathmell, 2013).”