t0901317 and Stomach-Neoplasms

Liver X receptors (LXRs) are involved in various diseases associated with lipid disorders, and in regulating cancer cell proliferation. However, the underlying molecular mechanisms, especially those in gastric cancer (GC) remain to be clarified. In this study, immunohistochemistry analysis revealed that LXRβ was mainly expressed in GC tissue, with less expression in adjacent normal tissues. The LXRβ agonist T0901317 efficiently suppressed the proliferation and colony formation of various GC cell lines. We further showed that LXRβ translocated from the cytoplasm to the nucleus when activated by T0901317. LXRβ nuclear localization suppressed the activation of Wnt signalling and decreased the expression of target genes such as MYC, BMP4, and MMP7 through binding to their promoters. Moreover, we demonstrated that the LXR agonist efficiently suppressed GC tumour growth in a nude mouse xenograft model. Taken together, these results revealed that LXRβ agonist inhibited GC cells proliferation by suppressing Wnt signalling via LXRβ relocalization. The results strongly suggest that LXRβ could be a promising target in GC therapy.

Topics: Aged; Animals; Anticholesteremic Agents; Antineoplastic Agents; Bone Morphogenetic Protein 4; Cell Line, Tumor; Cell Movement; Cell Nucleus; Cell Proliferation; Cytoplasm; Female; Gene Expression Regulation, Neoplastic; Humans; Hydrocarbons, Fluorinated; Liver X Receptors; Male; Matrix Metalloproteinase 7; Mice; Mice, Nude; Middle Aged; Promoter Regions, Genetic; Protein Binding; Protein Transport; Proto-Oncogene Proteins c-myc; Stomach Neoplasms; Sulfonamides; Tumor Burden; Wnt Signaling Pathway; Xenograft Model Antitumor Assays