Ethyl pyruvate suppresses the growth, invasion and migration and induces the apoptosis of non‑small cell lung cancer cells via the HMGB1/RAGE axis and the NF‑κB/STAT3 pathway

Abstract

As an inhibitor of high mobility group protein B1 (HMGB1), ethyl pyruvate (EP) has been associated with various inflammatory diseases. Recent studies have investigated the relationship between EP and cancer. The present study aimed to determine the antitumor efficacy of EP in non-small cell lung cancer (NSCLC) cells and elucidate the underlying mechanism. A549, H520 and PC-9 cells were treated with EP in suitable concentrations. RT-qPCR and western blot analysis were performed to evaluate HMGB1 and RAGE expression levels. MTT and colony formation assays assessed the effect of EP on cell growth. A Transwell assay was used to evaluate invasion and migration potential and flow cytometry was performed to analyze cell apoptosis. Bcl-2 family proteins were identified by western blot analysis. The results demonstrated that an increased EP concentration effectively reduced HMGB1 and RAGE expression, thus inhibiting the HMGB1/RAGE axis. EP decreased level of PCNA and MMP-9 and increased P53 levels. Bcl-2 and Mcl-1 were also decreased, whereas Bax expression was increased. Furthermore, a high concentration of EP (30 mmol/l) significantly inhibited NF-κB and STAT3 activation. In summary, EP inhibited NSCLC cell growth, invasion and migration and induced apoptosis by suppressing the HMGB1/RAGE axis and the NF-κB/STAT3 pathway, thus suggesting that EP may be a valuable therapeutic agent for NSCLC.

High mobility group box 1 (HMGB1): a pivotal regulator of hematopoietic malignancies

“…Moreover, EP reverses the HMGB1-induced senescent phenotype of BM-MSCs and prolongs the survival of MRL/lpr mice [93]. EP also impairs HMGB1 secretion, leading to reduced RAGE expression and NF-κB/ STAT3 pathway activation [185]. As an antioxidant, quercetin promotes apoptosis by attenuating the expression of HMGB1 and RAGE and suppressing the activation of NF-κB in MCF-7 cells [186].…”

Ethyl pyruvate inhibits glioblastoma cells migration and invasion through modulation of NF-κB and ERK-mediated EMT

“…EP induces apoptosis and cell-cycle arrest in G phase in hepatocellular carcinoma cells by inhibiting the HMGB1-RAGE and AKT pathways (Cheng et al, 2014); EP suppresses growth and invasion of gallbladder cancer cells via downregulation of HMGB1-RAGE axis (Li et al, 2012). Similarly, in the cytoplasm of lung cancer, EP suppressed the growth, invasion and migration and induced apoptosis of NSCLC cells via the HMGB1/RAGE axis and the NF-κB/STAT3 pathway (Liu et al, 2019). EP can also regulate the gastric cancer cell cycle by regulating the P53 signaling pathway (Zhang et al, 2016).…”

Downregulation of high mobility group box 1 enhances the radiosensitivity of non‑small cell lung cancer by acting as a crucial target of microRNA‑107

“…Previous studies have reported that HMGB1 is upregulated in NSCLC and may induce the tumorigenesis and metastasis of lung cancer ( 26-28 ). In the present study, HMGB1 expression was notably downregulated in the serum of patients with NSCLC after radiotherapy, suggesting that conventional radiotherapy reduces HMGB1-associated radioresistance, thus inhibiting tumor growth.…”