EGFR induces PKM2 via PKCϵ-mediated NF-κB activation to promote glycolysis and tumor growth.

  • Major finding: EGFR induces PKM2 via PKCϵ-mediated NF-κB activation to promote glycolysis and tumor growth.

  • Mechanism: Monoubiquitinated PKCϵ activates IKKβ, leading to RelA-HIF1-α-driven PKM2 transcription.

  • Impact: Blockade of components of this EGFR-NF-κB pathway may suppress PKM2-stimulated tumor growth.

Upregulation of the M2 isoform of pyruvate kinase (PKM2) in tumors promotes aerobic glycolysis, resulting in increased proliferation and tumor growth. However, although PKM2 is regulated by alternative splicing, the mechanisms that control PKM2 transcription are unclear. Yang and colleagues investigated whether EGF receptor (EGFR) activation, which is common in human cancers, modulates PKM2 expression. EGFR activation induced PKM2 but not PKM1 mRNA expression in glioblastoma cells; this effect was blocked by protein kinase C (PKC) or NF-κB inhibition, suggesting that these pathways contribute to EGF-stimulated PKM2 expression. In support of this idea, EGF treatment enhanced the activity of inhibitor of κ light polypeptide gene enhancer in B cells, kinase β (IKKβ), which triggers NF-κB activation. Intriguingly, IKKβ activation occurred independently of inflammatory stimuli such as TNF-α and was instead mediated by the novel PKC isoform, PKCϵ, which directly phosphorylated IKKβ at the plasma membrane identifying a distinct mechanism of NF-κB activation. Induction of this pathway was dependent on upstream phospholipase C (PLC) γ1 activity and PKCϵ monoubiquitination in response to EGF, which facilitated PKCϵ interaction with NF-κB essential modulator (NEMO), a critical regulator of IKKβ activation. In addition, PKM2 upregulation required interaction of the NF-κB transcription factor v-rel reticuloendotheliosis viral oncogene homolog A (RelA) with the coactivator hypoxia-inducible factor 1α (HIF-1α) at the PKM promoter. Importantly, depletion of PKM2, RelA, or PKCϵ blocked EGFR-driven aerobic glycolysis and tumor growth in mice. Furthermore, high PKM2 expression levels were correlated with EGFR and IKKβ activity in human glioblastoma samples and were associated with poor patient prognosis, indicating that PKM2 may be a potential biomarker. These results delineate a signaling cascade connecting EGFR to NF-κB activation and suggest that inhibition of components of this pathway may impair cancer cell metabolism and thereby restrict tumor growth.

Yang W, Xia Y, Cao Y, Zheng Y, Bu W, Zhang L, et al. EGFR-induced and PKCϵ monoubiquitylation-dependent NK-κB activation upregulates PKM2 expression and promotes tumorigenesis. Mol Cell 2012 Oct 30 [Epub ahead of print].

©2012 American Association for Cancer Research.
2012