jsh-23 and Carcinoma--Squamous-Cell

The aim of this study is to evaluate the efficacy of insulin-like growth factor 1 receptor (IGF-1R) inhibitor Linsitinib, in esophageal squamous cell carcinoma (ESCC), and to characterize special biomarker to screen Linsitinib-sensitive patients as well as explore the molecular-resistant mechanism to Linsitinib in ESCC. Our study evaluated the sensitivity of insulin-like growth factor 1 receptor (IGF-1R) inhibitor, Linsitinib in ESCC cells with MTT assay. After Linsitinib treatment, the expressions of downstream signaling molecules and apoptosis pathways were measured by western blot. And the antitumor effect of Linsitinib and JSH-23, an inhibitor of nuclear factor-κB transcriptional activity, was analyzed both as single agent and in combination in ESCC. Apoptosis, cell viability, and clonogenic survival analysis were also investigated. The sensitivity of Linsitinib was relatively variable in patient-derived primary ESCC cells as well as in human commercial cell lines. And the downstream AKT/mTOR and ERK signaling pathways were inhibited by Linsitinib, while phosphorylation level of NF-κB p65 was obviously activated to reduce apoptosis effect in Linsitinib-resistant cell lines. Most importantly, blockage of NF-κB activity by JSH-23 could sensitize resistant cells to Linsitinib treatment. Results from this study demonstrated that the intrinsic resistance to Linsitinib was predominantly mediated by NF-κB activation in ESCC. Moreover, combination of Linsitinib and JSH-23 as therapy provides a novel strategy to overcome resistance to Linsitinib in ESCC.

Topics: Antineoplastic Agents; Apoptosis; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Survival; Drug Resistance, Neoplasm; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Extracellular Signal-Regulated MAP Kinases; Humans; Imidazoles; Interleukin-6; Interleukin-8; NF-kappa B; Phenylenediamines; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Pyrazines; RNA, Messenger; Signal Transduction; TOR Serine-Threonine Kinases; Tumor Cells, Cultured

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