Department of Medical Pathology and Laboratory Medicine, 4645 2nd Ave, Research Building III, University of California, Davis Health Systems, Sacramento, CA 95817, USA.
Biochem Pharmacol. 2013 Apr 1;85(7):1007-17. doi: 10.1016/j.bcp.2013.01.023. Epub 2013 Feb 8.
Fenretinide is significantly more effective in inducing apoptosis in cancer cells than all-trans retinoic acid (ATRA). The current study uses a genome-wide approach to understand the differential role fenretinide and ATRA have in inducing apoptosis in Huh7 cells. Fenretinide and ATRA-induced gene expressions and DNA bindings were profiled using microarray and chromatin immunoprecipitation with anti-RXRα antibody. The data showed that fenretinide was not a strong transcription regulator. Fenretinide only changed the expressions of 1 093 genes, approximately three times less than the number of genes regulated by ATRA (2 811). Biological function annotation demonstrated that both fenretinide and ATRA participated in pathways that determine cell fate and metabolic processes. However, fenretinide specifically induced Fas/TNFα-mediated apoptosis by increasing the expression of pro-apoptotic genes i.e., DEDD2, CASP8, CASP4, and HSPA1A/B; whereas, ATRA induced the expression of BIRC3 and TNFAIP3, which inhibit apoptosis by interacting with TRAF2. In addition, fenretinide inhibited the expression of the genes involved in RAS/RAF/ERK-mediated survival pathway. In contrast, ATRA increased the expression of SOSC2, BRAF, MEK, and ERK genes. Most genes regulated by fenretinide and ATRA were bound by RXRα, suggesting a direct effect. This study revealed that by regulating fewer genes, the effects of fenretinide become more specific and thus has fewer side effects than ATRA. The data also suggested that fenretinide induces apoptosis via death receptor effector and by inhibiting the RAS/RAF/ERK pathway. It provides insight on how retinoid efficacy can be improved and how side effects in cancer therapy can be reduced.
芬维 A 酯在诱导癌细胞凋亡方面比全反式维 A 酸（ATRA）更为有效。本研究采用全基因组方法，研究芬维 A 酯和 ATRA 在诱导 Huh7 细胞凋亡方面的差异作用。采用微阵列和抗 RXRα 抗体的染色质免疫沉淀技术，分析芬维 A 酯和 ATRA 诱导的基因表达和 DNA 结合。结果表明，芬维 A 酯不是一个强转录调控因子。芬维 A 酯仅改变了 1093 个基因的表达，大约是 ATRA 调控基因数量（2811 个）的三分之一。生物功能注释表明，芬维 A 酯和 ATRA 均参与了决定细胞命运和代谢过程的途径。然而，芬维 A 酯通过增加促凋亡基因如 DEDD2、CASP8、CASP4 和 HSPA1A/B 的表达，特异性诱导 Fas/TNFα介导的凋亡；而 ATRA 则通过与 TRAF2 相互作用，诱导 BIRC3 和 TNFAIP3 的表达，从而抑制凋亡。此外，芬维 A 酯抑制了 RAS/RAF/ERK 介导的存活途径相关基因的表达。相反，ATRA 增加了 SOSC2、BRAF、MEK 和 ERK 基因的表达。芬维 A 酯和 ATRA 调节的大多数基因都与 RXRα 结合，表明存在直接作用。本研究表明，通过调节较少的基因，芬维 A 酯的作用更加特异，因此比 ATRA 的副作用更少。研究结果还表明，芬维 A 酯通过死亡受体效应诱导凋亡，并抑制 RAS/RAF/ERK 途径。该研究为如何提高视黄酸的疗效以及如何减少癌症治疗的副作用提供了思路。
