PKM2 activation sensitizes cancer cells to growth inhibition by 2-deoxy-D-glucose

Sui Seng Tee, Jae Mo Park, Ralph E. Hurd, Kyle R. Brimacombe, Matthew B. Boxer, Tarik F. Massoud, Brian K. Rutt, Daniel M. Spielman

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Cancer metabolism has emerged as an increasingly attractive target for interfering with tumor growth. Small molecule activators of pyruvate kinase isozyme M2 (PKM2) suppress tumor formation but have an unknown effect on established tumors. We demonstrate that TEPP-46, a PKM2 activator, results in increased glucose consumption, providing the rationale for combining PKM2 activators with the toxic glucose analog, 2-deoxy-D-glucose (2-DG). Combination treatment resulted in reduced viability of a range of cell lines in standard cell culture conditions at concentrations of drugs that had no effect when used alone. This effect was replicated in vivo on established subcutaneous tumors. We further demonstrated the ability to detect acute metabolic differences in combination treatment using hyperpolarized magnetic resonance spectroscopy (MRS). Combination treated tumors displayed a higher pyruvate to lactate 13C-label exchange 2 hr post-treatment. This ability to assess the effect of drugs non-invasively may accelerate the implementation and clinical translation of drugs that target cancer metabolism.

Original languageEnglish (US)
Pages (from-to)90959-90968
Number of pages10
JournalOncotarget
Volume8
Issue number53
DOIs
StatePublished - Jan 1 2017

Keywords

  • Cancer metabolism
  • Hyperpolarized MRI
  • Metabolic imaging
  • Molecular imaging
  • PKM2

ASJC Scopus subject areas

  • Oncology

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    Tee, S. S., Park, J. M., Hurd, R. E., Brimacombe, K. R., Boxer, M. B., Massoud, T. F., Rutt, B. K., & Spielman, D. M. (2017). PKM2 activation sensitizes cancer cells to growth inhibition by 2-deoxy-D-glucose. Oncotarget, 8(53), 90959-90968. https://doi.org/10.18632/oncotarget.19630