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

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 1α (PP1α) was activated by RSV, as indicated by a reduction in PP1α phosphorylation at T320. Pretreatment of cells with tautomycin, a selective PP1α 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 PP1α activity, thereby potentiating 2-DG-induced ER stress and NB cell death.

The Effect of a Novel c.820C>T (Arg274Trp) Mutation in the Mitofusin 2 Gene on Fibroblast Metabolism and Clinical Manifestation in a Patient

“…In contrast, only a minority, of between 14 to 20%, of control cells contained a network of slightly enlarged ER cisterns. The glucose-free condition, regarded as causing ER stress [44] led to notable ER enlargement in controls, encompassing >80% of cells; while aggravating pathological morphology in proband-derived cells, among which more than 90% of cells had dramatic broadening and fusion of the endoplasmic reticulum. Furthermore, western blotting analysis showed marked enhancement of GRP78/BiP in control cells, while in proband-derived cells the changes were less profound as compared with glucose-containing cultures.…”

5‐Azacytydine and resveratrol reverse senescence and ageing of adipose stem cells via modulation of mitochondrial dynamics and autophagy

“…Our data are in line with Gaballah et al, who observed that RES exerted modulatory effects on ER stress‐associated apoptosis in rats with rotenone‐induced Parkinson's disease. However, there are conflicting data implicating that RES can triggered ER stress However, increased ER stress caused by RES occurred mostly in cancer cell lines and was strictly correlated with polyphenol concentration and time of supplementation. We investigated whether disturbances in IR and FOXO‐1 expression occurred in ASCs EMS , because ER appeared to act directly as a negative regulator of insulin signalling pathway .…”

Resveratrol alleviates FFA and CCl4 induced apoptosis in HepG2 cells via restoring endoplasmic reticulum stress

“…However, the regulatory effect of RSV on ER stress is relatively complex. Cancer research has indicated that RSV plays a role in inducing ER stress to promote cancer cell apoptosis [ 21 – 23 ]. Other research has shown that RSV improves cardiomyocyte hypertrophy and inflammation via inhibiting ER stress [ 24 – 26 ].…”