Digestive Diseases and Nutrition Section, Department of Medicine and Cancer Center, University of Illinois at Chicago, 840 South Wood Street (M/C 716), Chicago, IL 60612, USA.
Br J Nutr. 2012 Jun;107(11):1591-602. doi: 10.1017/S0007114511004910. Epub 2011 Sep 29.
Several studies have suggested that the partially fermentable fibre Plantago ovata husk (PO) may have a protective effect on colorectal cancer (CRC). We studied the potentially pro-apoptotic effect of PO and the implicated mechanisms in CRC cells with different molecular phenotypes (Caco-2, HCT116, LoVo, HT-29, SW480) after PO anaerobic fermentation with colonic bacteria as it occurs in the human colon. The fermentation products of PO induced apoptosis in all primary tumour and metastatic cell lines, independent of p53, adenomatous polyposis coli, β-catenin or cyclo-oxygenase-2 status. Apoptosis was caspase-dependent and both intrinsic and extrinsic pathways were implicated. The intrinsic pathway was activated through a shift in the balance towards a pro-apoptotic environment with an up-regulation of B-cell lymphoma protein 2 homologous antagonist killer (BAK) and a down-regulation of B-cell lymphoma-extra large (Bcl-xL) seen in HCT116 and LoVo cells. This resulted in mitochondrial membrane depolarisation, increased expression of caspase activators second mitochondria-derived activator of caspases (Smac)/Diablo, death effector apoptosis-inducing factor, apoptosome member apoptotic protease activating factor 1 and down-regulation of inhibitors of apoptosis Survivin and X-linked inhibitor of apoptosis in most cells. The extrinsic pathway was activated presumably through the up-regulation of death receptor (DR5). Some important differences were seen between primary tumour and metastatic CRC cells. Thus, metastatic PO-treated LoVo cells had a remarkable up-regulation of TNF-α ligand along with death-inducing signalling complex components receptor interacting protein and TNF-α receptor 1-associated death domain protein. The extrinsic pathway modulator FCICE-inhibitory protein (FLIP), an inhibitor of both spontaneous death ligand-independent and death receptor-mediated apoptosis, was significantly down-regulated after PO treatment in all primary tumour cells, but not in metastatic LoVo. These findings suggest that PO could potentially be a useful chemotherapy adjuvant.
几项研究表明，部分可发酵纤维车前子壳（PO）可能对结直肠癌（CRC）具有保护作用。我们研究了 PO 与结肠细菌的厌氧发酵产物（如在人类结肠中发生的那样）对具有不同分子表型的 CRC 细胞（Caco-2、HCT116、LoVo、HT-29、SW480）的潜在促凋亡作用及其相关机制。PO 的发酵产物可诱导所有原发性肿瘤和转移性细胞系发生凋亡，这与 p53、腺瘤性结肠息肉病、β-连环蛋白或环氧化酶-2 状态无关。凋亡依赖于半胱天冬酶，并涉及内在和外在途径。内在途径通过向促凋亡环境的平衡转变而被激活，这种转变表现为 B 细胞淋巴瘤蛋白 2 同源拮抗剂杀手（BAK）的上调和 HCT116 和 LoVo 细胞中 B 细胞淋巴瘤-extra large（Bcl-xL）的下调。这导致线粒体膜去极化，增加第二线粒体衍生的半胱天冬酶激活物（Smac）/二价体、死亡效应物凋亡诱导因子、凋亡体成员凋亡蛋白酶激活因子 1 的表达和凋亡抑制剂 Survivin 和 X 连锁凋亡抑制剂的下调。在大多数细胞中。外在途径可能通过死亡受体（DR5）的上调而被激活。在原发性肿瘤和转移性 CRC 细胞之间观察到一些重要差异。因此，转移性 PO 处理的 LoVo 细胞具有 TNF-α配体的显著上调，同时还有死亡诱导信号复合物成分受体相互作用蛋白和 TNF-α受体 1 相关死亡域蛋白。外在途径调节剂 FCICE 抑制蛋白（FLIP）是一种对自发性死亡配体非依赖性和死亡受体介导的凋亡均有抑制作用的抑制剂，在所有原发性肿瘤细胞中，PO 处理后其表达显著下调，但在转移性 LoVo 细胞中却没有。这些发现表明，PO 可能是一种有用的化疗辅助剂。
