Kilarkaje Narayana, Al-Bader Maie
Department of Anatomy, Faculty of Medicine, Kuwait University, Safat, Kuwait
Department of Physiology, Faculty of Medicine, Kuwait University, Safat, Kuwait.
Toxicol Ind Health. 2016 Jan;32(1):89-97. doi: 10.1177/0748233713498441. Epub 2013 Sep 10.
Metastasis-associated protein 1 (MTA1) is involved in tumor growth and metastasis of cancers. Being a component of nucleosome remodeling and histone deacetylase complex, the protein is also associated with DNA damage response pathway. Since the protein is involved in cancer pathology, we first investigated the effects of bleomycin, etoposide, and cisplatin (BEP) on MTA1 signaling in the testis. Second, since the antioxidants (AOs) have protective effects, we further investigated whether or not an AO cocktail modulates the effects of the drugs. Adult male Sprague Dawley rats (N = 4) were treated either with saline, or AO (α-tocopherol, l-ascorbic acid, zinc, and selenium), or therapeutic dose levels of etoposide (15 mg/kg) and cisplatin (3 mg/kg) from day 1-4 of the week and B (1.5 mg/kg) on the second day of the week, or BEP + AO. The real-time polymerase chain reaction showed that MTA1 and MTA1s (short form) gene expression was downregulated in AO (100% and 100%), BEP (86% and 71%), and BEP + AO (97% and 93%) groups. Western blotting and immunohistochemistry results showed that unnormalized MTA1 protein expression was upregulated in AO (38%) and BEP + AO (34%) groups; however, the MTA1/β-actin ratio was upregulated in all treated groups (21, 19, and 15%, respectively). In conclusion, the results indicate that both BEP and AO suppress MTA1 and MTA1s transcription, which may render the germ cells to be more prone to apoptosis. However, upregulation of MTA1 protein expression may be related to induced DNA damage. Modulation of MTA1 signaling is a novel mechanism of action of BEP and AO, which may be useful in developing newer anticancer drugs.
转移相关蛋白1（MTA1）参与癌症的肿瘤生长和转移。作为核小体重塑和组蛋白去乙酰化酶复合物的一个组成部分，该蛋白还与DNA损伤反应途径相关。由于该蛋白参与癌症病理过程，我们首先研究了博来霉素、依托泊苷和顺铂（BEP）对睾丸中MTA1信号传导的影响。其次，由于抗氧化剂（AO）具有保护作用，我们进一步研究了AO混合物是否能调节这些药物的作用。成年雄性Sprague Dawley大鼠（N = 4）在一周的第1 - 4天接受生理盐水、AO（α-生育酚、l-抗坏血酸、锌和硒）、治疗剂量水平的依托泊苷（15 mg/kg）和顺铂（3 mg/kg）以及在一周的第二天接受博来霉素（1.5 mg/kg），或BEP + AO处理。实时聚合酶链反应显示，AO组（100%和100%）、BEP组（86%和71%）以及BEP + AO组（97%和93%）中MTA1和MTA1s（短形式）基因表达下调。蛋白质印迹和免疫组织化学结果显示，AO组（38%）和BEP + AO组（34%）中未标准化的MTA1蛋白表达上调；然而，所有处理组中MTA1/β-肌动蛋白比值均上调（分别为21%、19%和15%）。总之，结果表明BEP和AO均抑制MTA1和MTA1s转录，这可能使生殖细胞更容易发生凋亡。然而，MTA1蛋白表达上调可能与诱导的DNA损伤有关。MTA1信号传导的调节是BEP和AO的一种新作用机制，这可能有助于开发更新的抗癌药物。
