Mitochondrial Peroxiredoxin III is a Potential Target for Cancer Therapy

Abstract

Mitochondria are involved either directly or indirectly in oncogenesis and the alteration of metabolism in cancer cells. Cancer cells contain large numbers of abnormal mitochondria and produce large amounts of reactive oxygen species (ROS). Oxidative stress is caused by an imbalance between the production of ROS and the antioxidant capacity of the cell. Several cancer therapies, such as chemotherapeutic drugs and radiation, disrupt mitochondrial homeostasis and release cytochrome c, leading to apoptosome formation, which activates the intrinsic pathway. This is modulated by the extent of mitochondrial oxidative stress. The peroxiredoxin (Prx) system is a cellular defense system against oxidative stress, and mitochondria in cancer cells are known to contain high levels of Prx III. Here, we review accumulating evidence suggesting that mitochondrial oxidative stress is involved in cancer, and discuss the role of the mitochondrial Prx III antioxidant system as a potential target for cancer therapy. We hope that this review will provide the basis for new strategic approaches in the development of effective cancer treatments.

Altered cellular redox homeostasis and redox responses under standard oxygen cell culture conditions versus physioxia

“…Importantly, the activities of key antioxidant enzymes involved in maintaining redox homeostasis and protecting against oxidative stress were significantly higher in cells cultured under hyperoxia (Fig. 4) and have previously been shown to confer resistance to photodynamic therapy, chemotherapy and radiotherapy both in vitro and in vivo [42][43][44][45][71][72][73]. Further investigation found that selective inhibitors of the Nrf2-regulated thioredoxin antioxidant system increased the efficacy of photodynamic cell killing under physioxia, but not under hyperoxia (Fig.…”

Overexpression of peroxiredoxin-3 and -5 is a potential biomarker for prognosis in endometrial cancer

“…These proteins are overexpressed in several types of malignancy, including breast cancer, mesothelioma, lung cancer, cervical cancer, prostate cancer, and multiple myeloma (31). Mitochondria in cancer cells are known to contain high levels of PRDX3 and PRDX5 (32)(33)(34)(35)(36), and Song et al (37) reported that the mitochondrial PRDX3 antioxidant system, which is exclusively present in mitochondria, may be a potential target for cancer therapy.…”

Detection and identification of peroxiredoxin 3 as a biomarker in hepatocellular carcinoma by a proteomic approach

“…Increased mitochondrial ROS generation and the disturbance of peroxiredoxin (Prx) production in cancer cells may lead to oxidative stress and hypoxic microenvironments, and subsequently to the induction of apoptosis (17). The upregulation of antioxidant enzymes, especially in mitochondria, would provide the tumor cells with certain survival advantages under their intrinsically high oxidative conditions (31).…”

“…As a mitochondrial protein and a c-Myc target gene, PRDX3 catalyzes the reduction of peroxides in the presence of thioredoxin, which is required for mitochondrial homeostasis and neoplastic transformation (17). PRDX3 is an important cellular antioxidant that regulates physiological levels of H 2 O 2 stress to protect cells against apoptosis induced by high levels of H 2 O 2 (25).…”