1,1-bis(3′-indolyl)-1-(p-substitutedphenyl)methanes induce peroxisome proliferator-activated receptor γ-mediated growth inhibition, transactivation, and differentiation markers in colon cancer cells
1,1-bis(3′-indolyl)-1-(p-substitutedphenyl)methanes induce peroxisome proliferator-activated receptor γ-mediated growth inhibition, transactivation, and differentiation markers in colon cancer cells
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DOI：
10.1158/0008-5472.can-04-0399
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发表时间：
2004-09-01
期刊：
影响因子：
11.2
通讯作者：
Safe, S
中科院分区：
文献类型：
--
作者：
Chintharlapalli, S;Smith, R;Safe, S
含有对三氟甲基（DIM-C-pPhCF（3））、对叔丁基（DIM-C-pPhtBu）和对苯基（DIM-C-pPhC（6）H（5））基团的1，1-双（3 '吲哚基）-1-（对取代苯基）甲烷在HT-29、HCT-15、RKO和SW 480结肠癌细胞系中诱导过氧化物酶体增殖物激活受体γ（PPARgamma）介导的反式激活。罗格列酮还诱导这些细胞系中的反式激活，并抑制表达野生型PPARgamma的HT-29细胞的生长，但不抑制表达突变型（K422 Q）PPARgamma的HCT-15细胞的生长。相反，DIM-C-pPhCF（3）、DIM-C-pPhtBu和DIM-C-pPhC（6）H（5）抑制HT-29和HCT-15细胞的生长，IC 50值范围为1 - 10 mumol/L。罗格列酮和二吲哚甲烷（DIM）类似物不影响HCT-15或HT-29细胞中细胞周期蛋白D1、p21或p27蛋白水平的表达或凋亡，但诱导两种细胞系中的角蛋白18。然而，罗格列酮在HT-29细胞中诱导小窝蛋白1和2，而在HCT-15细胞中不诱导，而这些分化标志物在两种细胞系中均由DIM-C-pPhCF 3和DIM-C-pPhC 6 H5诱导。因为已知小窝蛋白1的过表达抑制结肠癌细胞和肿瘤生长，所以罗格列酮和DIM化合物的生长抑制作用与小窝蛋白的PPARgamma依赖性诱导相关。
1,1-Bis(3'indolyl)-1-(p-substitutedphenyl)methanes containing p-trifluoromethyl (DIM-C-pPhCF(3)), p-t-butyl (DIM-C-pPhtBu), and p-phenyl (DIM-C-pPhC(6)H(5)) groups induce peroxisome proliferator-activated receptor gamma (PPARgamma)-mediated transactivation in HT-29, HCT-15, RKO, and SW480 colon cancer cell lines. Rosiglitazone also induces transactivation in these cell lines and inhibited growth of HT-29 cells, which express wild-type PPARgamma but not HCT-15 cells, which express mutant (K422Q) PPARgamma. In contrast, DIM-C-pPhCF(3), DIM-C-pPhtBu, and DIM-C-pPhC(6)H(5) inhibited growth of both HT-29 and HCT-15 cells with IC50 values ranging from 1 to 10 mumol/L. Rosiglitazone and diindolylmethane (DIM) analogues did not affect expression of cyclin D1, p21, or p27 protein levels or apoptosis in HCT-15 or HT-29 cells but induced keratin 18 in both cell lines. However, rosiglitazone induced caveolins 1 and 2 in HT-29 but not HCT-15 cells, whereas these differentiation markers were induced by DIM-C-pPhCF3 and DIM-C-pPhC6H5 in both cell lines. Because overexpression of caveolin 1 is known to suppress colon cancer cell and tumor growth, the growth inhibitory effects of rosiglitazone and the DIM compounds are associated with PPARgamma-dependent induction of caveolins.