bay-11-7082 and Carcinoma--Squamous-Cell

Oral cancer is one of the most common human malignancies, and its incidence is increasing worldwide. In particular, oral squamous cell carcinoma (OSCC) is characterized by high rates of proliferation, invasiveness, and metastasis. Currently, standard treatment for OSCC includes surgical removal, chemotherapy, and radiotherapy; however, the survival rate of patients with OSCC remains low, thus new therapies are needed. It has been proven that excessive NLRP3 inflammasome activation and apoptosis alteration may contribute to oral cancer progression. This study aimed to investigate the effect of BAY-117082, an NLRP3 inflammasome inhibitor, in an in vitro and in vivo xenograft model of oral cancer. In vitro results revealed that BAY-117082 at concentrations of 5, 10, and 30 µM was able to reduce OSCC cell viability. BAY-117082 at higher concentrations significantly reduced NLRP3, ASC, caspase-1, IL-1β, and IL-18 expression. Moreover, Bax, Bad, and p53 expression were increased, whereas Bcl-2 expression was reduced. Furthermore, the in vivo study demonstrated that BAY-117082 at doses of 2.5 and 5 mg/kg significantly decreased subcutaneous tumor mass, and also reduced NLRP3 inflammasome pathway activation. Therefore, based on these results, the use of BAY-117082 could be considered a promising strategy to counteract oral cancer progression, thanks its ability to modulate the NLRP3 inflammasome and apoptosis pathways.

Topics: Animals; Carcinoma, Squamous Cell; Cell Proliferation; Disease Progression; Humans; Inflammasomes; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Mouth Neoplasms; Nitriles; NLR Family, Pyrin Domain-Containing 3 Protein; Sulfones; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Long non-coding RNAs (lncRNAs) have emerged recently as key regulators of tumor development and progression. Our previous study identified an NF-KappaB interacting lncRNA (NKILA) which was negatively correlated with breast cancer metastasis and patient prognosis. However, its clinical significance and potential role in Tongue squamous cell carcinoma (TSCC) remain unclear. Here we show that NKILA is down-regulated in TSCC cancer tissues than that in matched adjacent noncancerous tissues. And low NKILA expression in TSCC is significantly correlated with tumor metastasis and poor patient prognosis. In vitro, overexpression of NKILA decreases TSCC cells migration and invasion. Mechanistic study shows that NKILA inhibits the phosphorylation of IκBα and NF-κB activation as well as the induction of the epithelial-mesenchymal transition (EMT) process. Ectopic expression of NKILA in Tscca cells inhibits NF-κB activator TNF-α-promoted cell migration and invasion, while applying NF-κB inhibitor Bay-117082 or JSH-23 in NKILA silenced CAL27 cells reverses cell migration capacity to lower level. In vivo experimental metastasis model also demonstrates NKILA inhibits lung metastasis of NOD/SCID mice with TSCC tumors. These results suggested that NKILA is a vital determinant of TSCC migration and invasion and NF-κB signaling pathway mediates this effect. Given the above mentioned function of NKILA, it could act as a potential predictor for overall survival in patients with TSCC and a potential therapeutic target for TSCC intervention.

Topics: Aged; Animals; Carcinoma, Squamous Cell; Cell Movement; Epithelial-Mesenchymal Transition; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Silencing; Humans; Lung Neoplasms; Male; Mice; Mice, Inbred NOD; Mice, SCID; Middle Aged; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Transplantation; NF-kappa B; Nitriles; Phenylenediamines; Prognosis; RNA, Long Noncoding; Sulfones; Tongue Neoplasms