From the Division of Life and Pharmaceutical Sciences.
Center for Cell Signaling and Drug Discovery Research, and.
J Biol Chem. 2011 Mar 11;286(10):8394-8404. doi: 10.1074/jbc.M110.179416. Epub 2010 Dec 9.
The 2-Cys peroxiredoxins (Prx) belong to a family of antioxidant enzymes that detoxify reactive oxygen and nitrogen species and are distributed throughout the intracellular and extracellular compartments. However, the presence and role of 2-Cys Prxs in the nucleus have not been studied. This study demonstrates that the PrxII located in the nucleus protects cancer cells from DNA damage-induced cell death. Although the two cytosolic 2-Cys Prxs, PrxI and PrxII, were found in the nucleus, only PrxII knockdown selectively and markedly increased cell death in the cancer cells treated with DNA-damaging agents. The increased death was completely reverted by the nuclearly targeted expression of PrxII in an activity-independent manner. Furthermore, the antioxidant butylated hydroxyanisole did not influence the etoposide-induced cell death. Mechanistically, the knockdown of Prx II expression impaired the DNA repair process by reducing the activation of the JNK/c-Jun pathway. These results suggest that PrxII is likely to be attributed to a tumor survival factor positively regulating JNK-dependent DNA repair with its inhibition possibly sensitizing cancer cells to chemotherapeutic agents.
2- 半胱氨酸过氧化物酶（Prx）属于抗氧化酶家族，可清除活性氧和氮物种，并分布于细胞内和细胞外区室。然而，细胞核中 2- 半胱氨酸 Prx 的存在和作用尚未得到研究。本研究表明，位于细胞核内的 PrxII 可保护癌细胞免受 DNA 损伤诱导的细胞死亡。虽然两种细胞质 2- 半胱氨酸 Prx（PrxI 和 PrxII）都存在于细胞核中，但只有 PrxII 敲低在经 DNA 损伤剂处理的癌细胞中选择性且显著增加细胞死亡。用活性非依赖性方式将 PrxII 靶向核表达完全逆转了增加的死亡。此外，抗氧化剂丁基羟基茴香醚不会影响依托泊苷诱导的细胞死亡。从机制上讲，Prx II 表达的敲低通过降低 JNK/c-Jun 途径的激活来损害 DNA 修复过程。这些结果表明，PrxII 可能是一种肿瘤生存因子，通过其抑制可能使癌细胞对化疗药物敏感，从而正向调节依赖 JNK 的 DNA 修复。
