Quercetin induced NUPR1-dependent autophagic cell death by disturbing reactive oxygen species homeostasis in osteosarcoma cells

Abstract

Osteosarcoma is a primary bone aggressive cancer, affecting adolescents worldwide. Quercetin (a natural polyphenolic com pound) is a polyphenolic flavonoid compound found in a variety of plants. It has been demonstrated to exert cytostatic activity against a variety of human cancer, including the human osteo sarcoma. However, its efficacy in the treatment of osteosarcoma and the underlying antitumor mechanism has not been fully elucidated yet. In this study, we exposed MG 63 cells to different concentrations of quercetin (50, 100 and 200 µM) for 24 h. Here, we show that quercetin increased autophagic flux in the MG 63 cells, as evidenced by the upregulation of LC3B II/LC3B I and downregulation of P62/SQSTM1. Moreover, the autophagy inhibitor Bafilomycin A1 or genetic blocking autophagy with ATG5 knock down decreased quercetin induced cell death, indicating quercetin triggered autophagic cell death in MG 63 cells. Specifically, quercetin increased NUPR1 expression and activated of NUPR1 reporter activity, which contributed to the expression of autophagy related genes and subsequent initiated autophagic cell death in osteo sarcoma cells. Importantly, the increased expression NUPR1 were tightly related to the disturbance of reactive oxygen species (ROS) homeostasis, which could be prevented by inhibiting intracellular ROS with NAC. Finally, NAC also abolished quercetin induced autophagic cell death in vivo. Taken together, these data demon strate that quercetin induces osteosarcoma cell death via inducing excessive autophagy, which is mediated through the ROS NUPR1 pathway. Quercetin application may be a promising and practical strategy for osteosarcoma treatment in clinical practice.

Human Endogenous Retrovirus (HERV)-K env Gene Knockout Affects Tumorigenic Characteristics of nupr1 Gene in DLD-1 Colorectal Cancer Cells

“…These data suggest that HERV-K env KO and down-regulation of NUPR1 may regulate the protein stability of RB protein. The functions of NUPR1 have been reported to be highly related to ROS generation, apoptosis induced by autophagy, and ER stress [26,27]. Therefore, the ROS-NUPR1 pathway was analyzed via ROS levels and related protein levels in HERV-K env KO cells.…”

Role of Phytochemicals in Perturbation of Redox Homeostasis in Cancer

“…It was observed that quercetin-induced overproduction of ROS led to increased expression and activation of NUPR1. Although a majority of the studies show an inverse relation between NUPR1 and ROS, a direct relation is hypothesized [ 115 , 116 ].…”

Plant Polyphenols for Aging Health: Implication from Their Autophagy Modulating Properties in Age-Associated Diseases

“…In addition, the co-treatment further enhanced quercetin-mediated LC3B expression along with an increase in p62, indicating that lysosomal inhibition plays a significant role in the death of glioma cells [ 164 ]. In osteosarcoma cells, quercetin treatment augmented NUPR-1-mediated autophagic cell death accompanied by the increase in ROS level [ 165 ]. Evidence indicates that NUPR-1 helps in the transcriptional activation of genes involved in autophagosome formation and is also involved in cell cycle regulation, DNA repair and apoptosis [ 166 , 167 ].…”