t0901317 and Lung-Neoplasms

Liver X receptors are recognized as important regulators of cholesterol, fatty acid metabolism, inflammatory responses, and glucose homeostasis. The antineoplastic properties of synthetic liver X receptor (LXR) agonists (T0901317 and GW3965) have been reported in human carcinomas. Epidermal growth factor tyrosine kinase inhibitor (EGFR-TKI) is a first-line treatment for non-small-cell lung cancer patients with EGFR mutations. We used scratch and transwell assays to analyze cell migration and invasion. We evaluated tumor migration and invasion in vitro using a fluorescent orthotopic lung cancer model. An MMP9 (mouse) enzyme-linked immunosorbent assay kit was used to measure serum MMP9 concentrations. Protein expression was identified by western blot assays. In this study, we determined the effects of T0901317 and/or an EGFR-TKI on the lung cancer cell lines A549 and HCC827-8-1 in vitro and in vivo. We confirmed that the combination of the LXR agonist T0901317 and gefitinib can inhibit the migration and invasion of lung cancer both in vivo and in vitro, and this effect was possibly achieved by the inhibition of the ERK/MAPK signaling pathway. Our study showed that the combination of the LXR agonist T0901317 and gefitinib can inhibit the migration and invasion of lung cancer both in vivo and in vitro.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Movement; Cell Proliferation; Female; Gefitinib; Humans; Hydrocarbons, Fluorinated; In Vitro Techniques; Liver X Receptors; Lung Neoplasms; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Invasiveness; Sulfonamides; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

The liver X receptors (LXRs) is an important component of the nuclear receptor (NR) superfamily. Previous studies have shown that the LXRs possessed antitumor activity in various types of tumor cells. However, the complicated mechanisms underlying the antitumor activity remain largely unexplored. In this study, we incubated A549 cells with the compound T0901317, a specific LXRs agonist, for 24 h. The MTT assay was used to assess cell viability. Transwell assays were used to evaluate cell migration and invasion. The shRNA was utilized for RNA interference. The target gene and protein expression levels were assessed using reverse transcription-PCR and western blot assay. The DNA-binding activity of nuclear factor κB (NF-κB) was examined using electrophoretic mobility shift assays. Luciferase reporter assay was used to detect the binding of NF-κB to the matrix metalloproteinase-9 (MMP-9) promoter. We found that T0901317 inhibited the invasion and migration of A549 cells in a dose-dependent manner. Meanwhile, we further indicated that activation of LXRβ, one subtype of LXRs, can downregulate MMP-9 expression. More importantly, activation of LXRβ triggered by T0901317 inhibited the invasion and metastasis of A549 cells by repressing NF-κB/MMP-9 signaling pathway. Taken together, our study shows that activation of LXRs triggered by T0901317 inhibits the invasion and metastasis of human non-small-cell lung cancer by repressing the NF-κB/MMP-9 signaling pathway.

Topics: A549 Cells; Carcinoma, Non-Small-Cell Lung; Cell Movement; Dose-Response Relationship, Drug; Down-Regulation; Humans; Hydrocarbons, Fluorinated; Liver X Receptors; Lung Neoplasms; Matrix Metalloproteinase 9; Neoplasm Invasiveness; NF-kappa B; Signal Transduction; Sulfonamides

Cancer heterogeneity is a big hurdle in achieving complete cancer treatment, which has led to the emergence of combinational therapy. In this study, we investigated the potential use of nuclear receptor (NR) ligands for combinational therapy with other anti-cancer drugs. We first profiled all 48 NRs and 48 biological anti-cancer targets in four pairs of lung cell lines, where each pair was obtained from the same patient. Two sets of cell lines were normal and the corresponding tumor cell lines while the other two sets consisted of primary versus metastatic tumor cell lines. Analysis of the expression profile revealed 11 NRs and 15 cancer targets from the two pairs of normal versus tumor cell lines, and 9 NRs and 9 cancer targets from the primary versus metastatic tumor cell lines had distinct expression patterns in each category. Finally, the evaluation of nuclear receptor ligand T0901317 for liver X receptor (LXR) demonstrated its combined therapeutic potential with tyrosine kinase inhibitors. The combined treatment of cMET inhibitor PHA665752 or EGFR inhibitor gefitinib with T0901317 showed additive growth inhibition in both H2073 and H1993 cells. Mechanistically, the combined treatment suppressed cell cycle progression by inhibiting cyclinD1 and cyclinB expression. Taken together, this study provides insight into the potential use of NR ligands in combined therapeutics with other biological anti-cancer drugs.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Cyclin B; Cyclin D1; ErbB Receptors; Gefitinib; Humans; Hydrocarbons, Fluorinated; Indoles; Liver X Receptors; Lung Neoplasms; Orphan Nuclear Receptors; Protein Kinase Inhibitors; Quinazolines; Receptors, Cytoplasmic and Nuclear; Sulfonamides; Sulfones