Hypoxia-mediated autophagic flux inhibits silver nanoparticle-triggered apoptosis in human lung cancer cells

Abstract

Solid tumors are frequently associated with resistance to chemotherapy because the fraction of hypoxic tumor cells is substantial. To understand the underlying mechanism of hypoxia on silver nanoparticle (AgNPs)-induced apoptosis, the expression of hypoxia-inducible factor (HIF)-1α, a hallmark of hypoxia, was measured in the presence and absence of AgNPs. The results showed that HIF-1α expression was upregulated after AgNPs treatment under both hypoxic and normoxic conditions. Cell viability assays showed that AgNPs promoted cell death in cancer cells but not in non-cancer cells, as cancer cells are slightly more acidic than normal cells. However, reactive oxygen species generation induced by AgNPs in lung cancer cells caused high susceptibility to oxidative stress, whereas pre-exposure to hypoxia blocked AgNPs-induced oxidative stress. Notably, HIF-1α inhibited AgNPs-induced mitochondria-mediated apoptosis by regulating autophagic flux through the regulation of ATG5, LC3-II, and p62. Further, cell viability after treatment of cancer cells with AgNPs under hypoxic conditions was lower in HIF-1α siRNA-transfected cells than in control siRNA-transfected cells, indicating that HIF-1α knockdown enhances hypoxia induced decrease in cell viability. Our results suggest that hypoxia-mediated autophagy may be a mechanism for the resistance of AgNPs-induced apoptosis and that strategies targeting HIF-1α may be used for cancer therapy.

Asymmetric dumbbell-shaped silver nanoparticles and spherical gold nanoparticles green-synthesized by mangosteen (<em>Garcinia mangostana</em>) pericarp waste extracts

“…29,30 Wang et al 29 reported green-synthesized AgNPs by Dendropanax morbifera leaf extract, and the AgNPs showed potent cytotoxicity toward the A549 cells. The extract of Dimocarpus 33 Therefore, asymmetric dumbbell-shaped …”

Dual functions of silver nanoparticles in F9 teratocarcinoma stem cells, a suitable model for evaluating cytotoxicity- and differentiation-mediated cancer therapy

“…Previously, we found that AgNPs induced mitochondrial-mediated apoptosis in A549 cells. 40,54,55 AgNPs treatment resulted in an increase in mitochondrial depolarization accompanied with decreased levels of ATP in human lung carcinoma cells. 45 A previous study also suggested that nanoparticles can enter mitochondria and induce the generation of ROS, thus potentiating structural damage and eventually leading to apoptosis.…”

Quercetin-mediated synthesis of graphene oxide&ndash;silver nanoparticle nanocomposites: a suitable alternative nanotherapy for neuroblastoma

“…The data showed that both GO-AgNPs and GO treatment caused a remarkable decrease of the aggregate ratio compared with that of the control, which suggested a reduction in MMP. Previously, several studies have reported that AgNPs have a potential impact on various types of cancer cells, including human lung cancer cells 17,66 and male germ cells. 67 Other studies showed that exposing cells to GO results in the perturbation of the mitochondrial structure and function, as characterized by a decrease in the MMP and the dysregulation of mitochondrial Ca 2+ homeostasis.…”