Thioredoxin reductase 1 ablation sensitizes colon cancer cells to methylseleninate-mediated cytotoxicity
Thioredoxin reductase 1 ablation sensitizes colon cancer cells to methylseleninate-mediated cytotoxicity
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DOI：
10.1016/j.taap.2009.09.010
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发表时间：
2009-12-15
影响因子：
3.8
通讯作者：
Moos, Philip J.
中科院分区：
文献类型：
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作者：
Honeggar, Matthew;Beck, Robert;Moos, Philip J.
硒与癌症之间的关系很复杂，因为血清硒水平低的人可以从补充硒中受益，但血清硒水平高的人患其他疾病的风险增加。这表明硒化合物的使用可能仅限于特定情况，如辅助治疗。这种二分法的一个贡献者可能是某些含硒酶的活性，如细胞溶质硫氧还蛋白还原酶（TR1）。我们评估了细胞反应，以选择硒化合物，具有抗癌活性时，TR1被削弱的siRNA在RKO结肠癌细胞。甲基亚硒酸（MSA）。其是TR1的底物，当TR1被减弱时，增强了对结肠癌细胞的细胞毒性。MSA诱导内质网应激，通过GRP78蛋白水平测定。然而，这一途径似乎没有考虑到细胞毒性的变化时，TR1被削弱。相反，敲除胞质TR加上与MSA孵育增加了自噬（如通过LOB切割所测量的）和凋亡（如通过膜联蛋白V和线粒体功能障碍所测量的）。因此，使用具有抗癌活性的硒化合物，如MSA，可能最有效地与化疗应用中靶向TR1的药物一起使用。(C)2009 Elsevier Inc. All rights reserved.
The relationship between selenium and cancer is complex because individuals with low serum selenium levels benefit from selenium supplementation, but those with high serum selenium levels are at increased risk for other diseases. This suggests that the use of selenocompounds might be limited to particular circumstances, such as adjuvant therapy. A contributor to this dichotomy may be the activity of certain selenium containing enzymes like the cytosolic thioredoxin reductase (TR1). We evaluated the cellular response to select selenocompounds that have anticancer activity when TR1 was attenuated by siRNA in RKO colon cancer cells. Methylseleninic acid (MSA). which is a substrate for TR1, enhanced cytotoxicity to colon cancer cells when TR1 was attenuated. MSA induced stress in the endoplasmic reticulum, as measured by GRP78 protein levels. However, this pathway did not appear to account for the change in cytotoxicity when TR1 was attenuated. Instead, knockdown of the cytosolic TR plus incubation with MSA increased autophagy, as measured by LOB cleavage, and apoptosis, as measured by Annexin V and mitochondrial dysfunction. Therefore, the use of selenocompounds with anticancer activity, like MSA, might be utilized most effectively with agents that targets TR1 in chemotherapeutic applications. (C) 2009 Elsevier Inc. All rights reserved.