Peroxiredoxin II Restrains DNA Damage-induced Death in Cancer Cells by Positively Regulating JNK-dependent DNA Repair

Kyung Wha Lee,Doo Jae Lee,Joo Young Lee,Sang Won Kang,Dong Hoon Kang,Jongbum Kwon

doi:10.1074/jbc.m110.179416

Abstract

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.

Highlights

Sclerosis, and neurological disorders [2, 3]
We found that the two isoforms of 2-Cys Prxs, PrxI and PrxII, are present in the nucleus and demonstrated that the nuclear PrxII prevents the cancer cell death induced by DNA-damaging agents, including topoisomerase inhibitors
PrxII Protects Cancer Cells from DNA Damage-induced Cell Death—We studied the role of the nuclear PrxI and PrxII in the cell death induced by DNA-damaging agents, including topoisomerase inhibitors, a replication blocker, and a DNA intercalating agent

Summary

Introduction

Sclerosis, and neurological disorders [2, 3]. In contrast, at relatively low levels, ROS are thought to be the second messenger that plays a key role in signaling events that induce proliferation, differentiation, and apoptosis [4, 5]. We found that the two isoforms of 2-Cys Prxs, PrxI and PrxII, are present in the nucleus and demonstrated that the nuclear PrxII prevents the cancer cell death induced by DNA-damaging agents, including topoisomerase inhibitors. The PrxII knockdown drastically enhanced the death of HeLa cancer cells in response to different DNA-damaging agents, such as etoposide, camptothecin, hydroxyurea, and doxorubicin (Fig. 2, B–E).

Results

Conclusion