Peroxiredoxin 1 knockdown potentiates  -lapachone cytotoxicity through modulation of reactive oxygen species and mitogen-activated protein kinase signals

Abstract

Peroxiredoxin (Prx) 1 is a member of the thiol-specific peroxidases family and plays diverse roles such as H2O2 scavenger, redox signal transducer and molecular chaperone. Prx1 has been reported to be involved in protecting cancer cells against various therapeutic challenges. We investigated how modulations of intracellular redox system affect cancer cell sensitivity to reactive oxygen species (ROS)-generating drugs. We observed that stable and transient Prx1 knockdown significantly enhanced HeLa cell sensitivity to β-lapachone (β-lap), a potential anticancer agent. Prx1 knockdown markedly potentiated 2 µM β-lap-induced cytotoxicity through ROS accumulation. This effect was largely NAD(P)H:quinone oxidoreductase 1 dependent and associated with a decrease in poly(ADP-ribose) polymerase 1 protein levels, phosphorylation of JNK, p38 and Erk proteins in mitogen-activated protein kinase (MAPK) pathways and a decrease in thioredoxin 1 (Trx1) protein levels. Trx1 serves as an electron donor for Prx1 and is overexpressed in Prx1 knockdown cells. Based on the fact that Prx1 is a major ROS scavenger and a partner of at least ASK1 and JNK, two key components of MAPK pathways, we propose that Prx1 knockdown-induced sensitization to β-lap is achieved through combined action of accumulation of ROS and enhancement of MAPK pathway activation, leading to cell apoptosis. These data support the view that modulation of intracellular redox state could be an alternative approach to enhance cancer cell sensitivity to ROS-generating drugs or to overcome some types of drug resistance.

Peroxiredoxin proteins protect MCF-7 breast cancer cells from doxorubicin-induced toxicity

“…For example, Wang et al showed that Prdx2 suppression in MCF-7 cells increased sensitivity to radiation-induced cell death (25), and a recent follow-up study demonstrated that this occurred by alterations in cellular thiol status and intracellular Ca 2+ homeostasis (32). Likewise, Prdx1 suppression in MCF-7 cells leads to apoptosis induced by β-lapachone, an anticancer agent that produces large amounts of ROS induced apoptosis (33). In addition, Bae et al showed that transgenic overexpression of Prdx1 and Prdx2 in MCF-10A cells increases their resistance to peroxide-induced cell death (22).…”

Roles of peroxiredoxins in cancer, neurodegenerative diseases and inflammatory diseases

“…Moreover, several studies demonstrated that overexpression of PRDX1 and PRDX2 has an important role in several drug resistances, and several therapeutic agents targeting PRDX1 and PRDX2 are studied for treatment of cancer. He et al showed that PRDX1 knockdown enhances sensitization to β-lap that is an anticancer agent through modulating ROS accumulation and MAPK activation (He et al, 2013). Also, downregulation of PRDX1 by a novel fully human phage display recombinant antibody induces apoptosis and enhances radiation sensitization in lung carcinoma cells (Guo et al, 2011), indicating that PRDX1 could be targets competing against cancer.…”

Expression and function of peroxiredoxins in gynecological malignancies

“…He et al (32) found that HeLa cell line with the peroxiredoxin 1 gene stably knockedown (peroxiredoxin 1-) exhibited increased sensitivity to β-lapachone, but not the other three ROS-generating agents as compared with a corresponding control cell line (peroxiredoxin 1+). Then β-lapachone was also reported to induce more death in peroxiredoxin 1−cells than peroxiredoxin 1+ cells.…”