Pierre Anne-Sophie, Minville-Walz Mélaine, Fèvre Cécile, Hichami Aziz, Gresti Joseph, Pichon Laurent, Bellenger Sandrine, Bellenger Jérôme, Ghiringhelli François, Narce Michel, Rialland Mickaël
Université de Bourgogne, Centre de Recherche INSERM, UMR866, 6 Boulevard Gabriel, 21000 Dijon, France.
Biochim Biophys Acta. 2013 Apr;1831(4):759-68. doi: 10.1016/j.bbalip.2013.01.005. Epub 2013 Jan 15.
Dietary conjugated linoleic acids (CLA) are fatty acid isomers with anticancer activities produced naturally in ruminants or from vegetable oil processing. The anticancer effects of CLA differ upon the cancer origin and the CLA isomers. In this study, we carried out to precise the effects of CLA isomers, c9,t11 and t10,c12 CLA, on mechanisms of cell death induction in colon cancer cells. We first showed that only t10,c12 CLA treatment (25 and 50μM) for 72h triggered apoptosis in colon cancer cells without affecting viability of normal-derived colon epithelial cells. Exposure of colon cancer cells to t10,c12 CLA activated ER stress characterized by induction of eIF2α phoshorylation, splicing of Xbp1 mRNA and CHOP expression. Furthermore, we evidenced that inhibition of CHOP expression and JNK signaling decreased t10,c12 CLA-mediated cancer cell death. Finally, we showed that CHOP induction by t10,c12 CLA was dependent on ROS production and that the anti-oxidant N-acetyl-cysteine reduced CHOP induction-dependent cell death. These results highlight that t10,c12 CLA exerts its cytotoxic effect through ROS generation and a subsequent ER stress-dependent apoptosis in colon cancer cells.
膳食共轭亚油酸（CLA）是反刍动物天然产生的或植物油加工过程中产生的具有抗癌活性的脂肪酸异构体。CLA的抗癌作用因癌症起源和CLA异构体而异。在本研究中，我们精确研究了CLA异构体c9,t11和t10,c12 CLA对结肠癌细胞死亡诱导机制的影响。我们首先表明，仅用t10,c12 CLA（25和50μM）处理72小时可诱导结肠癌细胞凋亡，而不影响正常来源的结肠上皮细胞的活力。将结肠癌细胞暴露于t10,c12 CLA会激活内质网应激，其特征在于eIF2α磷酸化的诱导、Xbp1 mRNA的剪接和CHOP表达。此外，我们证明抑制CHOP表达和JNK信号传导可降低t10,c12 CLA介导的癌细胞死亡。最后，我们表明t10,c12 CLA诱导的CHOP依赖于活性氧的产生，并且抗氧化剂N-乙酰半胱氨酸可减少CHOP诱导依赖性细胞死亡。这些结果突出表明，t10,c12 CLA通过活性氧的产生以及随后结肠癌细胞中内质网应激依赖性凋亡发挥其细胞毒性作用。
