PKM2 Isoform-Specific Deletion Reveals a Differential Requirement for Pyruvate Kinase in Tumor Cells

Koch Institute for Integrative Cancer Research at Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Cell (Impact Factor: 32.24). 10/2013; 155(2):397-409. DOI: 10.1016/j.cell.2013.09.025
Source: PubMed


The pyruvate kinase M2 isoform (PKM2) is expressed in cancer and plays a role in regulating anabolic metabolism. To determine whether PKM2 is required for tumor formation or growth, we generated mice with a conditional allele that abolishes PKM2 expression without disrupting PKM1 expression. PKM2 deletion accelerated mammary tumor formation in a Brca1-loss-driven model of breast cancer. PKM2 null tumors displayed heterogeneous PKM1 expression, with PKM1 found in nonproliferating tumor cells and no detectable pyruvate kinase expression in proliferating cells. This suggests that PKM2 is not necessary for tumor cell proliferation and implies that the inactive state of PKM2 is associated with the proliferating cell population within tumors, whereas nonproliferating tumor cells require active pyruvate kinase. Consistent with these findings, variable PKM2 expression and heterozygous PKM2 mutations are found in human tumors. These data suggest that regulation of PKM2 activity supports the different metabolic requirements of proliferating and nonproliferating tumor cells. PAPERCLIP:

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    • "Recent findings indicate, however, that cancer cells may be able to display more flexibility than perhaps anticipated. Indeed, a genetic study showed that cancer cells are capable of switching from anabolic production of biomass for cell division to more catabolic ATP generation for survival in conditions of energy stress [28]. Healthy ECs, by contrast, can plastically switch back and forth between quiescence and proliferation and can resort to quiescence in conditions of nutrient stress or blockade of a critical metabolic pathway. "
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    • "pyruvate kinase) less likely to exert control over the Warburg Effect 201 than others. Although the finding that pyruvate kinase typically does not exert substantial 202 control over glycolysis may appear surprising, this findings is consistent with studies that 203 have observed only modest changes in glycolytic flux due to changes in pyruvate kinase 204 activity(Christofk, Vander Heiden et al. 2008; Israelsen, Dayton et al. 2013). 205 To further investigate the contexts in which steps along glycolysis can be limiting, 206 we correlated the FCCs with one another and carried out a hierarchical clustering that 207 revealed modules of co-occurring flux control (Fig 3C). "
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    • "By using an elegant transgenic mouse model, it was shown that PKM2 deletion accelerates tumor formation in a BRCA1-deficient breast cancer mouse model, suggesting that PKM2 is not necessary for tumor cell proliferation. Furthermore , histology analyses revealed that the highly proliferative PKM2- deficient cancer cells decrease also the expression of the M1 variant of PK, PKM1, establishing an anticorrelation between PK activity and proliferation (Israelsen et al., 2013). Together, these results seem to suggest that PKM2 expression in tumors facilitates low PK activity, which is needed for cancer cells growth and proliferation. "
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