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Cancer metabolism

When more is less

A tightly regulated enzyme balances energy production and the synthesis of macromolecules from glucose in cancer cells. Upsetting this balance by stimulating the enzyme's activity can suppress tumour growth in mice.

The development of cancer is associated with a suite of metabolic changes that support the energetic and biosynthetic requirements of tumour-cell proliferation. Many of these changes are stimulated by the same genetic mutations that drive tumorigenesis, suggesting that normalizing the tumour cells' metabolism by pharmacological means could suppress cancer progression. An enhancement of glycolysis, a cellular pathway that produces both energy and precursors of macromolecules, is a classic metabolic hallmark of cancer, making the glycolytic pathway an attractive target in which to test this hypothesis. Writing in Nature Chemical Biology, Anastasiou et al.1 show that targeting a form of the enzyme pyruvate kinase that is commonly found in tumour cells can redistribute the fate of glucose-derived metabolites away from biosynthetic pathways, and suppress tumour growth in mice.

The ability of the glycolytic pathway to produce ATP — the main cellular energy-transfer molecule is largely dependent on the activity of pyruvate kinases. There are various mammalian forms of pyruvate kinase, and tumour cells typically express the M2 isoform (PKM2), which shows reduced enzyme activity compared with other pyruvate kinases. This was initially thought to be somewhat paradoxical in cancer cells, in which abundant expression of glucose transporters and glycolytic enzymes conspires to enhance overall glycolysis. But one advantage of a bottleneck at the end of an otherwise active pathway is to force some of the intermediates it produces to accumulate, analogous to a partially closed valve at the bottom of a column of fluid (Fig. 1). It is now thought that the aggregation of metabolites behind this valve may promote their transfer into accessory pathways, including those that generate macromolecular building blocks and other substrates needed for cellular replication2.

Figure 1: A metabolic bottleneck.

During glucose metabolism (glycolysis), the enzyme pyruvate kinase acts as a 'tap' that regulates the rate of flow out of the pathway. a, Cancer cells often express the M2 form of the enzyme (PKM2), which has lower enzymatic activity than other isoforms of pyruvate kinase. This, combined with the robust glycolysis that is also a hallmark of cancer cells, leads to an accumulation of glycolytic intermediates, including precursors of nucleic acids, lipids, serine, glycine and methyl groups. The accumulation in turn stimulates the biosynthetic pathways into which these intermediates feed, thereby contributing to the rapid cell proliferation seen in tumours. b, By contrast, enhancing pyruvate kinase activity by replacing PKM2 with the more active PKM1 isoform causes a decline in these pools of biosynthetic precursors and reduced cell proliferation3. Anastasiou et al.1 show that a similar tumour-suppressive effect can be achieved using small molecules that enhance PKM2 activity.

This explanation for the role of PKM2 in cancer gained momentum when it was demonstrated that replacing PKM2 in cancer cells with the more active PKM1 isoform resulted in higher overall activity of pyruvate kinase but reduced macromolecular synthesis and tumour growth in mice3. Further support came from studies showing that many of the processes that regulate PKM2 in cancer cells, such as binding of the enzyme by tyrosine-phosphorylated proteins, act to reduce rather than stimulate its enzymatic activity4,5.

A possible implication of this picture of cancer-cell glycolysis is that stimulating PKM2 activity — in effect, opening the floodgates — might impair tumour growth by reducing the availability of macromolecular precursors. Anastasiou et al. tested this idea by using small molecules that clamp the enzyme into a highly active tetramer configuration (a complex containing four subunits of the enzyme), and then analysing tumour-cell glycolysis. They found that cellular pools of glucose-dependent biosynthetic intermediates became depleted, and that flux through the pathways supplied by them was suppressed. Treatment with the PKM2 activator molecules also reduced the proliferation of cancer cells subjected to low oxygen levels, a condition that favours glycolysis. Finally, when the authors treated tumour-bearing mice by oral administration of PKM2 activators, they found suppressed levels of biosynthetic intermediates in the tumours, and substantially slower tumour growth. Importantly, the small molecules also rendered PKM2 insensitive to blockade by tyrosine-phosphorylated proteins, suggesting that the agents might provide durable metabolic effects even in tumours that are programmed to reduce the activity of pyruvate kinases.

These studies of PKM2 activation provide a foundation for broader investigations of metabolism and cancer biology. Anastasiou and colleagues' results indicate that PKM2 affects biosynthesis in more subtle ways than those shown in Figure 1. For example, they found that activating PKM2 reduces the flux from glucose metabolism to fatty-acid synthesis, a pathway typically thought to involve the formation of pyruvate (a glycolytic intermediate molecule) by pyruvate kinases. Together, these new data imply that submaximal PKM2 activity helps to channel metabolites into biosynthetic pathways through mechanisms that do not simply involve an accumulation of intermediates, but that are not yet fully understood. It will be interesting to test whether modulating glycolysis through PKM2 activation or other mechanisms can be extended to suppress the proliferation of cells under conditions of normal oxygen levels, because such suppression would also be desirable in fast-growing areas of tumours that are well perfused by oxygen.

The push to understand PKM2 function, and now to manipulate it to suppress tumour growth, emphasizes a shift in focus in cancer metabolism research. Since Otto Warburg's early experiments on tumour glycolysis in the 1920s, work in this field has largely centred on how tumours produce energy. But recent studies have taken a much broader view of the metabolic network in cancer cells, leading to a greater appreciation of the complexities of biosynthesis, reduction–oxidation homeostasis and other facets of metabolism that support cell survival and proliferation. These investigations have uncovered many unexpected roles for metabolism in cell signalling and the regulation of gene expression, extending the reach of metabolic enzymes into essentially every area of cell biology6. These newly identified functions are highly relevant to cancer. Consider, for example, that PKM2 also acts as an activator of gene expression, such that it has proliferation-promoting activities that are independent of its enzymatic function7.

Finally, Anastasiou et al. have illustrated an important concept in the metabolic control of tumorigenesis. They show that activating PKM2 suppresses cell proliferation — but severely inhibiting this enzyme is known to have similar effects, and can induce tumour regression in mice8,9. It is likely that the highest rates of cell proliferation are the result of a metabolic network in which a set of enzymes that, like PKM2, contribute to biosynthesis are precisely controlled, but whose maximal activation is counterproductive. These nodes may be the most easily disrupted control points in the metabolic network, and identifying them should offer the best opportunities for metabolic therapy in cancer.


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Correspondence to Lei Jiang.

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Competing interests

L.J. receives salary support from Janssen Pharmaceutica NV, Beerse, Belgium. R.J.D. is a consultant for Agios Pharmaceuticals, Cambridge, Massachusetts, and is on the scientific advisory board of Peloton Therapeutics, Dallas, Texas.

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Jiang, L., DeBerardinis, R. When more is less. Nature 489, 511–512 (2012).

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