Appierto V, Villani M G, Cavadini E, Lotan R, Vinson C, Formelli F
Chemopreventive Unit, Department of Experimental Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy.
Cell Death Differ. 2004 Mar;11(3):270-9. doi: 10.1038/sj.cdd.4401349.
Fenretinide (HPR), a synthetic retinoid that exhibits lower toxicity than other retinoids, has shown preventive and therapeutic activity against ovarian tumors. Although the growth inhibitory effects of HPR have been ascribed to its ability to induce apoptosis, little is known about the molecular mechanisms involved. Since the proto-oncogene c-Fos has been implicated in apoptosis induction, we analyzed its role in mediating HPR response in a human ovarian carcinoma cell line (A2780) sensitive to HPR apoptotic effect. In these cells, HPR treatment caused induction of c-Fos expression, whereas such an effect was not observed in cells made resistant to HPR-induced apoptosis (A2780/HPR). Moreover, in a panel of other human ovarian carcinoma cell lines, c-Fos inducibility and HPR sensitivity were closely associated. Ceramide, which is involved in HPR-induced apoptosis, was also involved in c-Fos induction because its upregulation by HPR was reduced by fumonisin B(1), a ceramide synthase inhibitor. The causal relationship between c-Fos induction and apoptosis was established by the finding of an increased apoptotic rate in cells overexpressing c-Fos. Similarly to that observed for c-Fos expression, HPR treatment increased c-Jun expression in HPR-sensitive but not in HPR-resistant cells, suggesting the involvement of the transcription factor activating protein 1 (AP-1) in HPR-induced apoptosis. In gene reporter experiments, HPR stimulated AP-1 transcriptional activity and potentiated the AP-1 activity induced by 12-tetradecanoylphorbol 13-acetate. Furthermore, inhibition of AP-1 DNA binding, by transfecting A2780 cells with a dominant-negative Fos gene, caused decreased sensitivity to HPR apoptotic effects. Overall, the results indicate that c-Fos plays a role in mediating HPR-induced growth inhibition and apoptosis in ovarian cancer cells and suggest that c-Fos regulates these processes as a member of the AP-1 transcription factor.
芬维A胺（HPR）是一种合成类视黄醇，其毒性低于其他类视黄醇，已显示出对卵巢肿瘤的预防和治疗活性。尽管HPR的生长抑制作用归因于其诱导细胞凋亡的能力，但对其中涉及的分子机制知之甚少。由于原癌基因c-Fos与细胞凋亡诱导有关，我们分析了其在对HPR凋亡效应敏感的人卵巢癌细胞系（A2780）中介导HPR反应的作用。在这些细胞中，HPR处理导致c-Fos表达的诱导，而在对HPR诱导的细胞凋亡产生抗性的细胞（A2780/HPR）中未观察到这种效应。此外，在一组其他人类卵巢癌细胞系中，c-Fos的诱导性与HPR敏感性密切相关。参与HPR诱导细胞凋亡的神经酰胺也参与了c-Fos的诱导，因为神经酰胺合酶抑制剂伏马菌素B1可降低HPR对其的上调作用。通过发现过表达c-Fos的细胞中凋亡率增加，确立了c-Fos诱导与细胞凋亡之间的因果关系。与c-Fos表达的情况类似，HPR处理增加了HPR敏感细胞而非HPR抗性细胞中的c-Jun表达，这表明转录因子激活蛋白1（AP-1）参与了HPR诱导的细胞凋亡。在基因报告实验中，HPR刺激AP-1转录活性并增强了由12-十四酰佛波醇-13-乙酸酯诱导的AP-1活性。此外，通过用显性负性Fos基因转染A2780细胞来抑制AP-1与DNA的结合，导致对HPR凋亡效应的敏感性降低。总体而言，结果表明c-Fos在介导HPR诱导的卵巢癌细胞生长抑制和细胞凋亡中起作用，并表明c-Fos作为AP-1转录因子的一员调节这些过程。
