Abstract
Upon growth factor stimulation or in some EGFR mutant cancer cells, PKM2 translocates into the nucleus to induce glycolysis and cell growth. Here, we report that nuclear PKM2 binds directly to poly-ADP ribose, and this PAR-binding capability is critical for its nuclear localization. Accordingly, PARP inhibition prevents nuclear retention of PKM2 and therefore suppresses cell proliferation and tumor growth. In addition, we found that PAR level correlates with nuclear localization of PKM2 in EGFR mutant brain and lung cancers, suggesting that PAR-dependent nuclear localization of PKM2 likely contributes to tumor progression in EGFR mutant glioblastoma and lung cancers. In addition, some EGFR-inhibitor-resistant lung cancer cells are sensitive to PARP inhibitors. Taken together, our data indicate that suppression of PKM2 nuclear function by PARP inhibitors represents a treatment strategy for EGFR-inhibitor-resistant cancers.
Highlights
Poly(ADP-robose) polymerase-1 (PARP1) or ADP-ribosyltransferase diphtheria toxin-like 1 (ARTD1) (Hottiger et al, 2010) is the most abundant and the best understood member of the 17 PARP family proteins
To test the possibility that Pyruvate kinase isoform M2 (PKM2) itself may be PARylated by PARP1, in vitro PARP1 PARylation assay was performed, and Histone-H3 was included as positive control for PARP1 substrate
We showed that PARP1 could ribosylate itself and Histone H3, but not PKM2 in vitro (Figure S1B), indicating that PKM2 is not a substrate of PARP1
Summary
Poly(ADP-robose) polymerase-1 (PARP1) or ADP-ribosyltransferase diphtheria toxin-like 1 (ARTD1) (Hottiger et al, 2010) is the most abundant and the best understood member of the 17 PARP family proteins. PARP1-dependent BER and BRCA-dependent homologous repair pathway have overlapping and redundant functions in DNA repair (Bryant et al, 2005; Farmer et al, 2005; Fong et al, 2009; Rouleau et al, 2010). Recent studies have revealed that various stimuli and post-translational modifications including FGFR1-mediated Y105 phosphorylation (Hitosugi et al, 2009), ERK1/2-dependent S37 phosphorylation (Yang et al, 2012b), and P300-dependent K433 acetylation (Lv et al, 2013) trigger PKM2 translocation into nucleus. Nuclear PKM2 functions as a protein kinase to phosphorylate STAT3 (Gao et al, 2012), Histone H3 (Yang et al, 2012a), and Bub (Jiang et al, 2014), all of which contribute to promoting tumor growth or proliferation
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