XPKM2 isoform-specific deletion reveals a differential requirement for pyruvate kinase in tumor cells

William J. Israelsen, Talya L. Dayton, Shawn M. Davidson, Brian P. Fiske, Aaron M. Hosios, Gary Bellinger, Jie Li, Yimin Yu, Mika Sasaki, James W. Horner, Laura N. Burga, Jianxin Xie, Michael J. Jurczak, Ronald A. Depinho, Clary B. Clish, Tyler Jacks, Richard G. Kibbey, Gerburg M. Wulf, Dolores Di Vizio, Gordon B. MillsLewis C. Cantley, Matthew G. Vander Heiden

    Research output: Contribution to journalArticle

    246 Scopus citations

    Abstract

    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

    Original languageEnglish (US)
    Pages (from-to)397
    Number of pages1
    JournalCell
    Volume155
    Issue number2
    DOIs
    StatePublished - Oct 10 2013

    ASJC Scopus subject areas

    • Biochemistry, Genetics and Molecular Biology(all)

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    Israelsen, W. J., Dayton, T. L., Davidson, S. M., Fiske, B. P., Hosios, A. M., Bellinger, G., Li, J., Yu, Y., Sasaki, M., Horner, J. W., Burga, L. N., Xie, J., Jurczak, M. J., Depinho, R. A., Clish, C. B., Jacks, T., Kibbey, R. G., Wulf, G. M., Di Vizio, D., ... Vander Heiden, M. G. (2013). XPKM2 isoform-specific deletion reveals a differential requirement for pyruvate kinase in tumor cells. Cell, 155(2), 397. https://doi.org/10.1016/j.cell.2013.09.025