Resveratrol augments ER stress and the cytotoxic effects of glycolytic inhibition in neuroblastoma by downregulating Akt in a mechanism independent of SIRT1

Regina M Graham, Fiorela Hernandez, Nataly Puerta, Guillermo De Angulo, Keith A Webster, Steven Vanni

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Cancer cells typically display increased rates of aerobic glycolysis that are correlated with tumor aggressiveness and a poor prognosis. Targeting the glycolytic pathway has emerged as an attractive therapeutic route mainly because it should spare normal cells. Here, we evaluate the effects of combining the inhibition of glycolysis with application of the polyphenolic compound resveratrol (RSV) in neuroblastoma (NB) cancer cell lines. Inhibiting glycolysis with 2-deoxy-D-glucose (2-DG) significantly reduced NB cell viability and was associated with increased endoplasmic reticulum (ER) stress and Akt activity. Administration of 2-DG increased the expression of the ER molecular chaperones GRP78 and GRP94, the prodeath protein C/EBP homology protein (CHOP) and the phosphorylation of Akt at S473, T450 and T308. Combined treatment with both RSV and 2-DG reduced GRP78, GRP94 and Akt phosphorylation but increased CHOP and NB cell death when compared with the administration of 2-DG alone. The selective inhibition of Akt activity also decreased 2-DG-induced GRP78 and GRP94 expression and increased CHOP expression, suggesting that Akt can modulate ER stress. Protein phosphatase 1 (PP1) was activated by RSV, as indicated by a reduction in PP1 phosphorylation at T320. Pretreatment of cells with tautomycin, a selective PP1 inhibitor, prevented the RSV-mediated decrease in Akt phosphorylation, suggesting that RSV enhances 2-DG-induced cell death by activating PP1 and downregulating Akt. The RSV-mediated inhibition of Akt in the presence of 2-DG was not prevented by the selective inhibition of SIRT1, a known target of RSV, indicating that the effects of RSV on this pathway are independent of SIRT1. We propose that RSV inhibits Akt activity by increasing PP1 activity, thereby potentiating 2-DG-induced ER stress and NB cell death.

Original languageEnglish (US)
Article numbere210
JournalExperimental and Molecular Medicine
Volume48
Issue number2
DOIs
StatePublished - Feb 5 2016

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Endoplasmic Reticulum Stress
Neuroblastoma
Deoxyglucose
Down-Regulation
Protein Phosphatase 1
Phosphorylation
CCAAT-Enhancer-Binding Proteins
Glycolysis
Cell death
Cells
Cell Death
Polyphenolic compounds
resveratrol
Neoplasms
Proteins
Endoplasmic Reticulum
Tumors
Cell Survival
Cell Line

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Molecular Medicine
  • Clinical Biochemistry

Cite this

Resveratrol augments ER stress and the cytotoxic effects of glycolytic inhibition in neuroblastoma by downregulating Akt in a mechanism independent of SIRT1. / Graham, Regina M; Hernandez, Fiorela; Puerta, Nataly; De Angulo, Guillermo; Webster, Keith A; Vanni, Steven.

In: Experimental and Molecular Medicine, Vol. 48, No. 2, e210, 05.02.2016.

Research output: Contribution to journalArticle

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