The SP/NK1R System-Mediated ROS Generation in GBM Cells through Inhibiting Glutaredoxin Protein

Abstract

Altered redox balance is among the main contributing factors developing glioblastoma multiforme (GBM), a highly aggressive grade IV brain tumor. Neuropeptide substance P (SP) plays a key role in modifying the cellular redox environment by activating the neurokinin-1 receptor (NK1R). In this study, we aimed to investigate the redox-modulating properties of both SP and a commercially available NK1R antagonist, aprepitant in GBM cells. To detect the effect of aprepitant on the viability of U87 glioblastoma cells, resazurin assay was applied. The level of intracellular ROS was assessed using 2′,7′-dichlorodihydrofluorescein diacetate (H2DCFDA) assay. The expression of glutaredoxin, a well-known redox-active protein, was measured by quantitative real-time polymerase chain reaction (qRT-PCR). Concurrently, the activity of glutaredoxin was also analyzed by a commercial kit (ZellBio GmbH). We found that SP increased the intracellular levels of reactive oxygen species (ROS) in U87 GBM cells, and aprepitant remarkably decreased this effect. We also explored the effects of SP/NK1R signaling on the glutaredoxin system as a major cellular redox buffer in GBM cells. SP reduced both expression and enzymatic activity of glutaredoxin, and these effects were significantly decreased by aprepitant. In conclusion, our results suggest a possible involvement of SP/NK1R signaling in GBM pathogenesis through oxidative stress and offering new insight for the application of aprepitant as a redox-modulating strategy in GBM patients.

EnvZ/OmpR Controls Protein Expression and Modifications in Cronobacter sakazakii for Virulence and Environmental Resilience

“…40 In this study, we confirmed that envZ/ompR affects desiccation tolerance by downregulating the maltodextrin-binding protein and influences protein oxidative stress by downregulating grxC. Glutaredoxin, found in both eukaryotes (such as GBM cells) 41 and prokaryotes (such as bifidobacteria), 42 is a conserved protein that maintains cellular redox balance. The maltodextrinbinding protein can protect the molecular structure of C. sakazakii under desiccation by binding maltodextrin.…”

Current Understanding of PCSK9 and Its Relevance to Cancer Prognosis and Immune Therapy: A Review

“…Immune checkpoints are potent antioxidant regulators that control cellular tolerance and prevent tumors. Immune checkpoints assist the immune system in response to infections and cancer, which may protect tissues from damage ( 11 - 13 ). The concept that the immune system might restrict tumor development and cancer, dates back to 1893, when William Cooley used live bacteria as an immunological stimulant to treat cancer patients ( 2 ).…”

Prognostic and Therapeutic Value of NK1R: Correlation between Function in Immune Infiltration and Expression in Tumor Microenvironment

“…For example, overexpressed NK1R is related to glioblastoma multiforme (GBM). NK1R-mediating in ammation release reactive oxygen species (ROS) through inhibiting expression and enzymatic activity of glutaredoxin in GBM, which promotes tumorigenesis by mutagenic effects 15,16 . Contrarily, NK1R downregulation is related to breast cancer 17 .…”