Retinol decreases β-catenin protein levels in retinoic acid-resistant colon cancer cell lines
Retinol decreases β-catenin protein levels in retinoic acid-resistant colon cancer cell lines
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DOI：
10.1002/mc.20280
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发表时间：
2007-04-01
影响因子：
4.6
通讯作者：
Lane, Michelle A.
中科院分区：
文献类型：
--
作者：
Dillard, Alice C.;Lane, Michelle A.
在大多数结肠癌病例中，β-连环蛋白信号传导途径调节异常，导致细胞核β-连环蛋白积聚和参与肿瘤进展的基因转录增加。本研究检测了视黄醇对三种全反式维甲酸（ATRA）耐药的人结肠癌细胞系HCT-116、WiDr和SW 620中β-连环蛋白水平的影响。用浓度递增的视黄醇处理各细胞系24或48 h。在所有细胞系中，视黄醇降低了β-连环蛋白水平，增加了泛素化β-连环蛋白。用蛋白酶体抑制剂MG 132治疗阻断了视黄醇诱导的β-连环蛋白的减少，表明视黄醇通过增加蛋白酶体降解来减少β-连环蛋白。多种途径将β-连环蛋白引导至蛋白酶体以进行降解，包括p53/Siah 1/腺瘤性结肠息肉病（APC）、Wnt/糖原合酶激酶-3 β/APC和类维生素A“X”受体（RXR）介导的途径。由于β-连环蛋白（HCT-116）、APC（SW 620）和p53（WiDr）的突变，只有RXR介导的途径在每个细胞系中保持功能。为了确定RXR是否促进β-连环蛋白降解，用RXR泛拮抗剂PA 452处理细胞，或用RXR α小干扰RNA（siRNA）转染细胞。RXR泛拮抗剂和RXR α siRNA降低了视黄醇降低β-连环蛋白水平的能力。核β-连环蛋白通过与T细胞因子/淋巴增强因子（TCF/LEF）蛋白相互作用诱导基因转录。视黄醇处理降低了TOPFIash报告构建体的转录和内源性β-连环蛋白靶基因，细胞周期蛋白D1和c-myc的mRNA水平。这些结果表明，视黄醇可能通过增加β-连环蛋白的蛋白酶体降解，通过一种可能涉及RXR的机制，减少结肠癌细胞的生长。(c)2007 Wiley-Liss，Inc.
The beta-catenin signaling pathway is dysiregulated in most cases of colon cancer resulting in an accumulation of nuclear beta-catenin and increased transcription of genes involved in tumor progression. This study examines the effect of retinol on beta-catenin protein levels in three all-trans retinoic acid (ATRA)-resistant human colon cancer cell lines: HCT-116, WiDr, and SW620. Each cell line was treated with increasing concentrations of retinol for 24 or 48 h. Retinol reduced beta-catenin protein levels and increased ubiquitinated beta-catenin in all cell lines. Treatment with the proteasomal inhibitor MG132 blocked the retinol-induced decrease in beta-catenin indicating retinol decreases beta-catenin by increasing proteasomal degradation. Multiple pathways direct beta-catenin to the proteasome for degradation including a p53/Siah1/adenomatous polyposis coli (APC), a Wnt/glycogen synthase kinase-3p/APC, and a retinoid "X" receptor (RXR)mediated pathway. Due to mutations in beta-catenin (HCT-116), APC (SW620), and p53 (WiDr), only the RXR-mediated pathway remains functional in each cell line. To determine if RXRs facilitate beta-catenin degradation, cells were treated with the RXR pan-antagonist, PA452, or transfected with RXR alpha small interfering RNA (siRNA). The RXR pan-antagonist and RXR alpha siRNA reduced the ability of retinol to decrease beta-catenin protein levels. Nuclear beta-catenin induces gene transcription via interaction with T cell factor/lymphoid enhancer factor (TCF/LEF) proteins. Retinol treatment decreased the transcription of a TOPFIash reporter construct and mRNA levels of the endogenous beta-catenin target genes, cyclin D1 and c-myc. These results indicate that retinol may reduce colon cancer cell growth by increasing the proteasomal degradation of beta-catenin via a mechanism potentially involving RXR. (c) 2007 Wiley-Liss, Inc.