PARP Inhibition Suppresses Growth of EGFR-Mutant Cancers by Targeting Nuclear PKM2

Nan Li, Lin Feng, Hui Liu, Jiadong Wang, Moses Kasembeli, My Kim Tran, David J. Tweardy, Steven Hsesheng Lin, Junjie Chen

Research output: Contribution to journal › Article

18 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)843-856
Number of pages14
JournalCell Reports
Volume15
Issue number4
DOIs
StatePublished - Apr 26 2016

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Tumors
Cells
Poly Adenosine Diphosphate Ribose
Lung Neoplasms
Cell proliferation
Cell growth
Growth
Brain
Neoplasms
Intercellular Signaling Peptides and Proteins
Glycolysis
Glioblastoma
Brain Neoplasms
Cell Proliferation
Poly(ADP-ribose) Polymerase Inhibitors

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

PARP Inhibition Suppresses Growth of EGFR-Mutant Cancers by Targeting Nuclear PKM2. / Li, Nan; Feng, Lin; Liu, Hui; Wang, Jiadong; Kasembeli, Moses; Tran, My Kim; Tweardy, David J.; Lin, Steven Hsesheng; Chen, Junjie.

In: Cell Reports, Vol. 15, No. 4, 26.04.2016, p. 843-856.

Research output: Contribution to journal › Article

Li, N, Feng, L, Liu, H, Wang, J, Kasembeli, M, Tran, MK, Tweardy, DJ, Lin, SH & Chen, J 2016, 'PARP Inhibition Suppresses Growth of EGFR-Mutant Cancers by Targeting Nuclear PKM2', Cell Reports, vol. 15, no. 4, pp. 843-856. https://doi.org/10.1016/j.celrep.2016.03.070
Li N, Feng L, Liu H, Wang J, Kasembeli M, Tran MK et al. PARP Inhibition Suppresses Growth of EGFR-Mutant Cancers by Targeting Nuclear PKM2. Cell Reports. 2016 Apr 26;15(4):843-856. https://doi.org/10.1016/j.celrep.2016.03.070
Li, Nan ; Feng, Lin ; Liu, Hui ; Wang, Jiadong ; Kasembeli, Moses ; Tran, My Kim ; Tweardy, David J. ; Lin, Steven Hsesheng ; Chen, Junjie. / PARP Inhibition Suppresses Growth of EGFR-Mutant Cancers by Targeting Nuclear PKM2. In: Cell Reports. 2016 ; Vol. 15, No. 4. pp. 843-856.
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AU - Feng, Lin

AU - Liu, Hui

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AU - Kasembeli, Moses

AU - Tran, My Kim

AU - Tweardy, David J.

AU - Lin, Steven Hsesheng

AU - Chen, Junjie

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AB - 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.

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