Stigliano A, Cerquetti L, Borro M, Gentile G, Bucci B, Misiti S, Piergrossi P, Brunetti E, Simmaco M, Toscano V
Endocrinology, II Faculty of Medicine, S Andrea Hospital, Sapienza University of Rome, Rome, Italy.
Endocr Relat Cancer. 2008 Mar;15(1):1-10. doi: 10.1677/ERC-07-0003.
Mitotane, 1,1-dichloro-2-(o-chlorophenyl)-2-(p-chloro-phenyl) ethane (o,p'-DDD), is a compound that represents the effective agent in the treatment of the adrenocortical carcinoma (ACC), able to block cortisol synthesis. In this type of cancer, the biological mechanism induced by this treatment remains still unknown. In this study, we have already shown a greater impairment in the first steps of the steroidogenesis and recognized a little effect on cell cycle. We also evaluated the variation of proteomic profile of the H295R ACC cell line, either in total cell extract or in mitochondria-enriched fraction after treatment with mitotane. In total cell extracts, triose phosphate isomerase, alpha-enolase, D-3-phosphoglycerate dehydrogenase, peroxiredoxin II and VI, heat shock protein 27, prohibitin, histidine triad nucleotide-binding protein, and profilin-1 showed a different expression. In the mitochondrial fraction, the following proteins appeared to be down regulated: aldolase A, peroxiredoxin I, heterogenous nuclear ribonucleoprotein A2/B1, tubulin-beta isoform II, heat shock cognate 71 kDa protein, and nucleotide diphosphate kinase, whereas adrenodoxin reductase, cathepsin D, and heat shock 70 kDa protein 1A were positively up-regulated. This study represents the first proteomic study on the mitotane effects on ACC. It permits to identify some protein classes affected by the drug involved in energetic metabolism, stress response, cytoskeleton structure, and tumorigenesis.
米托坦，即1,1-二氯-2-(邻氯苯基)-2-(对氯苯基)乙烷（邻，对'-滴滴滴），是一种用于治疗肾上腺皮质癌（ACC）的有效化合物，能够阻断皮质醇的合成。在这类癌症中，这种治疗所诱导的生物学机制仍不清楚。在本研究中，我们已经表明在类固醇生成的第一步存在更大的损伤，并认识到其对细胞周期的影响较小。我们还评估了米托坦处理后H295R ACC细胞系在总细胞提取物或富含线粒体的组分中的蛋白质组学图谱变化。在总细胞提取物中，磷酸丙糖异构酶、α-烯醇化酶、D-3-磷酸甘油酸脱氢酶、过氧化物酶II和VI、热休克蛋白27、抑制素、组氨酸三联体核苷酸结合蛋白和丝切蛋白-1表现出不同的表达。在线粒体组分中，以下蛋白质似乎下调：醛缩酶A、过氧化物酶I、不均一核核糖核蛋白A2/B1、微管蛋白-β同工型II、热休克同源71 kDa蛋白和核苷二磷酸激酶，而肾上腺皮质铁氧化还原蛋白还原酶、组织蛋白酶D和热休克70 kDa蛋白1A则呈正向上调。本研究是关于米托坦对ACC作用的首次蛋白质组学研究。它有助于识别受该药物影响的一些蛋白质类别，这些蛋白质涉及能量代谢、应激反应、细胞骨架结构和肿瘤发生。
