Suppressive effect of nobiletin, a citrus polymethoxyflavonoid that downregulates thioredoxin-interacting protein expression, on tunicamycin-induced apoptosis in SK-N-SH human neuroblastoma cells

• Tunicamycin is a potent inducer of ER stress.
• Tunicamycin treatment induced TXNIP expression in a human neuroblastoma cell line.
• Nobiletin repressed TXNIP gene and protein expression in our previous data.
• Nobiletin suppressed the apoptosis and TXNIP expression induced by tunicamycin.
• Nobiletin may suppress ER stress by reducing TXNIP expression.

Increased expression of thioredoxin-interacting protein (TXNIP) has recently been proved to be a crucial event for irremediable endoplasmic reticulum (ER) stress resulting in the programmed cell death (apoptosis) of pancreatic β-cells. The present study demonstrated that treatment with 1–10 μg/ml tunicamycin, a potent revulsant of ER stress, drastically induced TXNIP expression accompanied by the generation of cleaved caspase-3 as an indicator of apoptosis in SK-N-SH human neuroblastoma cells. This result substantiated that TXNIP is also involved in neurodegeneration triggered by ER stress. Moreover, we evaluated the effects of nobiletin, a citrus polymethoxyflavonoid, on tunicamycin-induced apoptosis and TXNIP expression in SK-N-SH cells, because we reported previously that this flavonoid might be able to reduce TXNIP expression. Co-treatment of SK-N-SH cells with 100 μM nobiletin and 1 μg/ml tunicamycin for 24 h strongly suppressed apoptosis and increased TXNIP expression induced by 1 μg/ml tunicamycin treatment alone. In addition, we proved that the ability of 100 μM nobiletin treatment to reduce TXNIP expression is exerted from 3 h after the onset of treatment. Therefore, the protective and ameliorative effects of nobiletin on neuronal degeneration and impaired memory, which several studies using animal models have demonstrated, might arise in part from nobiletin's ability to repress TXNIP expression