Therapeutic potential of targeting MKK3-p38 axis with Capsaicin for Nasopharyngeal Carcinoma.

Background: Capsaicin is an active compound found in plants of the Capsicum genus; it has a range of therapeutic benefits, including anti-tumor effects. Here we aimed to delineate the inhibitory effects of capsaicin on nasopharyngeal carcinoma (NPC). Methods: The anti-cancer effects of capsaicin were confirmed in NPC cell lines and xenograft mouse models, using CCK-8, clonogenic, wound-healing, transwell migration and invasion assays. Co-immunoprecipitation, western blotting and pull-down assays were used to determine the effects of capsaicin on the MKK3-p38 axis. Cell proliferation and EMT marker expression were monitored in MKK3 knockdown (KD) or over-expression NPC cell lines treated with or without capsaicin. Finally, immunohistochemistry was performed on NPC specimens from NPC patients (n = 132) and the clinical relevance was analyzed. Results: Capsaicin inhibited cell proliferation, mobility and promoted apoptosis in NPC cells. Then we found that capsaicin directly targets p38 for dephosphorylation. As such, MKK3-induced p38 activation was inhibited by capsaicin. Furthermore, we found that capsaicin-induced inhibition of cell motility was mediated by fucokinase. Xenograft models demonstrated the inhibitory effects of capsaicin treatment on NPC tumor growth in vivo, and analysis of clinical NPC samples confirmed that MKK3 phosphorylation was associated with NPC tumor growth and lymphoid node metastasis. Conclusions: The MKK3-p38 axis represents a potential therapeutic target for capsaicin. MKK3 phosphorylation might serve as a biomarker to identify NPC patients most likely to benefit from adjunctive capsaicin treatment.

Chiang C ，Zhang M ，Wang D ，Xiao T ，Zhu L ，Chen K ，Huang J ，Huang J ，Zhu J ，Li L ，Chen C ，Chen Y ，Hu H ，Jiang W ，Zou Y ，Wang T ，Zheng D ... -  《Theranostics》

Capsaicin enhances cisplatin-induced anti-metastasis of nasopharyngeal carcinoma by inhibiting EMT and ERK signaling via serpin family B member 2.

Cisplatin (DDP)-based combined chemotherapy or concurrent chemoradiotherapy is the mainstay treatment for advanced-stage nasopharyngeal carcinoma (NPC), but needs improvement due to its severe side effects. Capsaicin (CAP) can enhance the anti-tumor activity of cytotoxic drugs. The aim of this study was to investigate the anti-metastasis activity of CAP in combination with DDP in NPC. Herein, CAP and DDP showed synergistic cytotoxic effects on NPC cells. CAP alone and DDP alone inhibited NPC migration and invasion in vitro and in vivo, and the combination of CAP and DDP had the greatest effect. Moreover, CAP upregulated the mRNA and protein expressions of serpin family B member 2 (SERPINB2). Further results showed that both SERPINB2 mRNA and protein expressions were downregulated in NPC cell lines and tissues and SERPINB2 overexpression inhibited NPC migration and invasion in vitro and in vivo, while silencing SERPINB2 acted oppositely. In addition, SERPINB2 was abnormally expressed in head and neck squamous cell carcinoma and other multiple cancers, and downregulation of SERPINB2 predicted poor prognosis in head and neck squamous cell carcinoma according to the Cancer Genome Atlas database. We further found that SERPINB2 overexpression inhibited epithelial-mesenchymal transition (EMT) and the phosphorylated extracellular signal-regulated kinase (p-ERK), and the inhibitory effect was enhanced by CAP and DDP. Altogether, our results suggest that the combined inhibition of CAP and DDP on NPC metastasis may be related to the inhibition of epithelial-mesenchymal transition and ERK signals mediated by SERPINB2, and CAP may help to improve the efficacy of DDP in the treatment of NPC and develop new therapeutic approaches.

Xu Y ，Kong W ，Zhao S ，Xiong D ，Wang Y ... -  《-》

Tolfenamic Acid Inhibits the Proliferation, Migration, and Invasion of Nasopharyngeal Carcinoma: Involvement of p38-Mediated Down-Regulation of Slug.

Jittreetat T ，Shin YS ，Hwang HS ，Lee BS ，Kim YS ，Sannikorn P ，Kim CH ... -  《-》

Short-term stimulation with histone deacetylase inhibitor trichostatin a induces epithelial-mesenchymal transition in nasopharyngeal carcinoma cells without increasing cell invasion ability.

Shen Z ，Liao X ，Shao Z ，Feng M ，Yuan J ，Wang S ，Gan S ，Ha Y ，He Z ，Jie W ... -  《-》

APLNR is involved in ATRA-induced growth inhibition of nasopharyngeal carcinoma and may suppress EMT through PI3K-Akt-mTOR signaling.

Liu Y ，Liu Q ，Chen S ，Liu Y ，Huang Y ，Chen P ，Li X ，Gao G ，Xu K ，Fan S ，Zeng Z ，Xiong W ，Tan M ，Li G ，Zhang W ... -  《-》