Resveratrol triggers the ER stress-mediated intrinsic apoptosis of neuroblastoma cells coupled with suppression of Rho-dependent migration and consequently prolongs mouse survival

Neuroblastoma, the most common childhood tumor, are highly malignant and fatal because neuroblastoma cells extremely defend against apoptotic targeting. Traditional treatments for neuroblastomas are usually ineffective and lead to serious side effects and poor prognoses. In this study, we investigated the molecular mechanisms of resveratrol-induced insults to neuroblastoma cells and survival extension of nude mice with neuroblastomas, especially in the endoplasmic reticular (ER) stress-intracellular reactive oxygen species (iROS) axis-mediated signals. Resveratrol specifically killed neuroblastoma cells mainly via apoptosis and autophagy rather than ne-crosis. As to the mechanisms, resveratrol time-dependently triggered productions of Grp78 protein and iROS in neuroblastoma cells. Attenuating the ER stress-iROS signaling axis significantly suppressed resveratrol-induced autophagy, DNA damage, and cell apoptosis. Successively, resveratrol decreased phosphorylation of retino-blastoma protein and induced cell cycle arrest at the S phase, translocation of Bak protein to mitochondria, a reduction in the mitochondrial membrane potential, cascade activation of caspases-9,-3, and-6, and DNA fragmentation. Moreover, weakening the ER stress-iROS axis concomitantly overcome resveratrol-induced de -creases in translocation of Rho protein to membranes and succeeding cell migration. Interestingly, administra-tion of resveratrol did not cause significant side effects but could protect the neuroblastoma-bearing nude mice from body weight loss and consequently extended the animal survival. In parallel, resveratrol elevated levels of Grp78 and then induced cell apoptosis in neuroblastoma tissues. This study has shown that resveratrol could kill neuroblastoma cells and extend survival of animals with neuroblastomas by triggering the ER stress-iROS-involved intrinsic apoptosis and suppression of Rho-dependent cell migration. Our results imply the potential of resveratrol as a drug candidate for chemotherapy of neuroblastoma patients.

Automated summary

This study investigated the effect of resveratrol on neuroblastoma cells and the survival of mice with neuroblastomas. Resveratrol induced apoptosis and autophagy in neuroblastoma cells and triggered ER stress and iROS production. It also suppressed cell migration by inhibiting the ER stress-iROS axis. Resveratrol had minimal side effects and extended the survival of neuroblastoma-bearing mice. This research suggests that resveratrol could be a potential drug candidate for neuroblastoma chemotherapy.