gw-3965 and Stomach-Neoplasms

Recently, great advances have been achieved in both surgery and chemotherapy for the treatment of gastric cancer, but there is still poor prognosis for this disease. The aim of this study is to investigate the role of liver X receptor β (LXRβ) in chemosensitivity of gastric cancer SGC7901 cells. From 171 patients with gastric cancer, the gastric cancer and paracancerous tissues were selected to measure the expression of LXRβ and ATF4. Gastric cancer cell lines were cultured and screened to figure out the proliferation and apoptosis of gastric cancer SGC7901 cells with the treatment of LXRβ agonist (GW3965), ATF4 short hairpin RNA (shRNA), and chemotherapy drug paclitaxel. The expression of apoptosis-related gene cleaved caspase-3 was detected by Western blot analysis. First, we found that the expressions of LXRβ and ATF4 in gastric cancer tissues and cells were significantly lower than those in their paracancerous tissues and gastric mucosal epithelial cells. In addition, activation of LXRβ and paclitaxel treatment suppressed proliferation of SGC7901 cells, and the expression of ATF4 was upregulated in a concentration-dependent manner. Furthermore, shRNA significantly inhibited the expression of ATF4 and blocked the chemosensitivity of SGC7901 cells to LXRβ activation. Our study demonstrates that the expression of LXRβ was low in gastric cancer. In addition, activation of LXRβ may inhibit the proliferation of gastric cancer cells, promote apoptosis, and increase chemosensitivity by upregulating the expression of ATF4.

Topics: Activating Transcription Factor 4; Adult; Aged; Apoptosis; Benzoates; Benzylamines; Cell Line; Cell Line, Tumor; Cell Proliferation; Drug Synergism; Female; Gene Expression Regulation, Neoplastic; Humans; Liver X Receptors; Male; Middle Aged; Paclitaxel; RNA Interference; Stomach Neoplasms; Up-Regulation

To examine the expression of liver X receptor-β (LXR-β) in human gastric cancer tissue, and to explore the effect of GW3965, an agonist of LXRs, on proliferation of gastric cancer cell line SGC-7901.
. The immunohistochemical assay was used to detect the expression of LXR-β, activating transcription factor 4 (ATF4) in gastric cancer tissues and the corresponding pericarcinoma tissues in 114 patients. Real-time quantitative PCR and Western blot were used to determine mRNA and protein levels of ATF4 and ATP-binding cassette 1 (ABCA1), one of the downstream target genes of LXRs, in SGC-7901 cells with or without GW3965 treatment. Cell counting kit-8 (CCK-8) assay was performed to detect cell proliferation. The expression of ATF4 was silenced by short hairpin RNA (shRNA).
. The expressions of LXR-β and ATF-4 were obviously down-regulated in the gastric cancer tissues than that in the corresponding pericarcinoma tissues (both P<0.05). Compared with the control cells, GW3965 treatment inhibited proliferation of SGC-7901 cells and up-regulated ATF4 and ABCA1 expressions (both P<0.05). Knockdown of ATF4 can reverse the antiproliferative effect of GW3965 on SGC-7901 cells.
. The expression of LXR-β is decreased in human gastric cancer tissues, and activation of LXRs by GW3965 could inhibit the proliferation of SGC-7901 cells via ATF4.. 目的：探讨肝X受体-β(liver X receptor-β，LXR-β)在胃癌组织中的表达及其激动剂GW3965对胃癌细胞SGC-7901增殖的影响。方法：应用免疫组织化学法检测114例胃癌及其对应的114例癌旁组织中增殖相关基因LXR-β和转录活化因子4(activating transcription factor 4，ATF4)的表达；培养胃癌细胞SGC-7901，待GW3965激活LXR-β后，应用qRT-PCR和Western印迹检测LXR-β下游基因三磷酸腺苷结合盒A1(ATP-binding cassette A1，ABCA1)和ATF4的表达，采用细胞增殖-毒性检测试剂盒检测细胞增殖情况；GW3965激活LXR-β后，利用ATF4短发夹RNA(short hairpin RNA，shRNA)靶向沉默ATF4，检测细胞增殖情况。结果：LXR-β和ATF4在胃癌组织中的表达均显著低于其相应的癌旁组织(均P<0.05)；GW3965激活LXR-β后，SGC7901细胞增殖明显受抑制，ABCA1和ATF4的表达明显上调(均P<0.05)；shRNA能显著抑制ATF4的表达，并阻断LXR-β激活后抑制细胞增殖的作用。结论：LXR-β在胃癌组织中呈低表达，活化的LXR-β可能通过ATF4抑制胃癌细胞的增殖。.

Topics: Activating Transcription Factor 4; Benzoates; Benzylamines; Cell Line, Tumor; Cell Proliferation; Gene Expression Regulation, Neoplastic; Gene Silencing; Humans; Liver X Receptors; Orphan Nuclear Receptors; RNA, Messenger; RNA, Small Interfering; Stomach Neoplasms; Up-Regulation