Biogenic selenium nanoparticles induce ROS-mediated necroptosis in PC-3 cancer cells through TNF activation

Abstract

BackgroundSelenium is well documented to inhibit cancer at higher doses; however, the mechanism behind this inhibition varies widely depending on the cell type and selenium species. Previously, we have demonstrated that Bacillus licheniformis JS2 derived biogenic selenium nanoparticles (SeNPs) induce non-apoptotic cell death in prostate adenocarcinoma cell line, PC-3, at a minimal concentration of 2 µg Se/ml, without causing toxicity to the primary cells. However, the mechanism behind its anticancer activity was elusive.ResultsOur results have shown that these SeNPs at a concentration of 2 µg Se/ml were able to induce reactive oxygen species (ROS) mediated necroptosis in PC-3 cells by gaining cellular internalization. Real-time qPCR analysis showed increased expression of necroptosis associated tumor necrotic factor (TNF) and interferon regulatory factor 1 (IRF1). An increased expression of RIP1 protein was also observed at the translational level upon SeNP treatment. Moreover, the cell viability was significantly increased in the presence of necroptosis inhibitor, Necrostatin-1.ConclusionData suggest that our biogenic SeNPs induce cell death in PC-3 cells by the ROS-mediated activation of necroptosis, independent to RIP3 and MLKL, regulated by a RIP1 kinase.

Specificity of Biogenic Selenium Nanoparticles for Prostate Cancer Therapy With Reduced Risk of Toxicity: An in vitro and in vivo Study

“…To dig into more detail, real-time gene expression analysis of characteristic genes of different cell death pathways showed over-expression of the only necroptosis associated TNF and IRF1 genes and downregulation of AR and PSA in these cells. The over-expression of TNF and IRF1 was found to be similar to our earlier observation in PC-3 cells (19). Further, the inhibition of SeNP induced cell death under the presence of necrostatin-1, a potent necroptosis inhibitor, confirmed the cell death pathway is necroptosis.…”

“…Similarly, biogenic SeNPs synthesized by Acinetobacter, Streptomyces, and Halococcus also showed anticancer activity, however, at higher doses (13)(14)(15). Earlier in our study, we have shown that a concentration of 2 µg Se/ml of our sterically stabilized biogenic SeNPs is very effective in inducing TNF/IRF1 mediated necroptosis in PC-3 cells without compromising the viability of human peripheral blood mononuclear cell (hPBMC) (18,19). In this part of the study, the effect of biogenic SeNPs on human prostate epithelial carcinoma cells, LNCaP was investigated.…”

“…Cells were seeded in RPMI 3160 medium at a density of 5 × 10 3 cells per well in 96-well flat bottom Nunclon Delta surface cell culture plates. After 24 h of resting period at 37 • C in a 5% CO 2 incubator, cells were treated with DMSO or 2 µg Se/ml SeNPs or 2 µg Se/ml SeNPs along with necrostatin-1 (Nec-1) at three different concentrations viz., 20, 50, or 100 mM and cultured for another 24 h at 37 • C. MTT assay for cell viability was performed as per our previously reported protocol (19).…”

Necrotic, apoptotic and autophagic cell fates triggered by nanoparticles

“…Moreover, recent evidence shows that cytotoxic effects of germanium NPs (4 nm) are blocked by necrostatin-1, suggesting that NPs may also induce necroptosis [87]. A very recent paper reports that selenium (Se) NPs induce ROS-mediated necroptosis in PC-3 cells following cellular internalization [88].…”

RIPK1 and RIPK3 - emerging targets in cancer?

“…These include, for example, disruption of the activity of the members of HOX family of transcription factors in AML (97); inhibition of Aurora kinase A in pancreatic carcinoma cells (98); PPARγ-induced Annexin A1 expression in triple negative breast cancer cells, promoting cIAP1-degradation and, thus, activation of RIPK1-dependent cell death (99); activation of MLKL by ceramide liposomes in ovarian carcinoma cells (100); induction of ROS-dependent TNFα synthesis and necroptosis by selenium nanoparticles in PC-3 human prostate cancer cells (101); and activation of mitochondrial stress and autophagy-dependent necroptosis by BH3 mimetic drug Obatoclax (GX15-070) in human oral cancer cells (102). These and other recent findings indicate that exciting new strategies to therapeutically activate RIPK1/ RIPK3-dependent pathways in human cancers may be possible in the near future, but further effort to translate these initial findings into clinically relevant approaches is required.…”