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Aerobic glycolysis suppresses p53 activity to provide selective protection from apoptosis upon loss of growth signals or inhibition of BCR-Abl.

Publication ,  Journal Article
Mason, EF; Zhao, Y; Goraksha-Hicks, P; Coloff, JL; Gannon, H; Jones, SN; Rathmell, JC
Published in: Cancer research
October 2010

Unlike the growth factor dependence of normal cells, cancer cells can maintain growth factor-independent glycolysis and survival through expression of oncogenic kinases, such as BCR-Abl. Although targeted kinase inhibition can promote cancer cell death, therapeutic resistance develops frequently, and further mechanistic understanding is needed. Cell metabolism may be central to this cell death pathway, as we have shown that growth factor deprivation leads to decreased glycolysis that promotes apoptosis via p53 activation and induction of the proapoptotic protein Puma. Here, we extend these findings to show that elevated glucose metabolism, characteristic of cancer cells, can suppress protein kinase Cδ (PKCδ)-dependent p53 activation to maintain cell survival after growth factor withdrawal. In contrast, DNA damage-induced p53 activation was PKCδ independent and was not metabolically sensitive. Both stresses required p53 Ser(18) phosphorylation for maximal activity but led to unique patterns of p53 target gene expression, showing distinct activation and response pathways for p53 that were differentially regulated by metabolism. Consistent with oncogenic kinases acting to replace growth factors, treatment of BCR-Abl-expressing cells with the kinase inhibitor imatinib led to reduced metabolism and p53- and Puma-dependent cell death. Accordingly, maintenance of glucose uptake inhibited p53 activation and promoted imatinib resistance. Furthermore, inhibition of glycolysis enhanced imatinib sensitivity in BCR-Abl-expressing cells with wild-type p53 but had little effect on p53-null cells. These data show that distinct pathways regulate p53 after DNA damage and metabolic stress and that inhibiting glucose metabolism may enhance the efficacy of and overcome resistance to targeted molecular cancer therapies.

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Published In

Cancer research

DOI

EISSN

1538-7445

ISSN

0008-5472

Publication Date

October 2010

Volume

70

Issue

20

Start / End Page

8066 / 8076

Related Subject Headings

  • src Homology Domains
  • bcl-X Protein
  • bcl-2-Associated X Protein
  • Tumor Suppressor Protein p53
  • Transfection
  • T-Lymphocytes
  • Reverse Transcriptase Polymerase Chain Reaction
  • Proto-Oncogene Proteins c-mdm2
  • Polymerase Chain Reaction
  • Plasmids
 

Citation

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Mason, E. F., Zhao, Y., Goraksha-Hicks, P., Coloff, J. L., Gannon, H., Jones, S. N., & Rathmell, J. C. (2010). Aerobic glycolysis suppresses p53 activity to provide selective protection from apoptosis upon loss of growth signals or inhibition of BCR-Abl. Cancer Research, 70(20), 8066–8076. https://doi.org/10.1158/0008-5472.can-10-0608
Mason, Emily F., Yuxing Zhao, Pankuri Goraksha-Hicks, Jonathan L. Coloff, Hugh Gannon, Stephen N. Jones, and Jeffrey C. Rathmell. “Aerobic glycolysis suppresses p53 activity to provide selective protection from apoptosis upon loss of growth signals or inhibition of BCR-Abl.Cancer Research 70, no. 20 (October 2010): 8066–76. https://doi.org/10.1158/0008-5472.can-10-0608.
Mason EF, Zhao Y, Goraksha-Hicks P, Coloff JL, Gannon H, Jones SN, et al. Aerobic glycolysis suppresses p53 activity to provide selective protection from apoptosis upon loss of growth signals or inhibition of BCR-Abl. Cancer research. 2010 Oct;70(20):8066–76.
Mason, Emily F., et al. “Aerobic glycolysis suppresses p53 activity to provide selective protection from apoptosis upon loss of growth signals or inhibition of BCR-Abl.Cancer Research, vol. 70, no. 20, Oct. 2010, pp. 8066–76. Epmc, doi:10.1158/0008-5472.can-10-0608.
Mason EF, Zhao Y, Goraksha-Hicks P, Coloff JL, Gannon H, Jones SN, Rathmell JC. Aerobic glycolysis suppresses p53 activity to provide selective protection from apoptosis upon loss of growth signals or inhibition of BCR-Abl. Cancer research. 2010 Oct;70(20):8066–8076.

Published In

Cancer research

DOI

EISSN

1538-7445

ISSN

0008-5472

Publication Date

October 2010

Volume

70

Issue

20

Start / End Page

8066 / 8076

Related Subject Headings

  • src Homology Domains
  • bcl-X Protein
  • bcl-2-Associated X Protein
  • Tumor Suppressor Protein p53
  • Transfection
  • T-Lymphocytes
  • Reverse Transcriptase Polymerase Chain Reaction
  • Proto-Oncogene Proteins c-mdm2
  • Polymerase Chain Reaction
  • Plasmids