Peroxiredoxins in Cancer and Response to Radiation Therapies

Abstract

Peroxiredoxins have a long-established cellular function as regulators of redox metabolism by catalyzing the reduction of peroxides (e.g., H2O2, lipid peroxides) with high catalytic efficiency. This activity is also critical to the initiation and relay of both phosphorylation and redox signaling in a broad range of pathophysiological contexts. Under normal physiological conditions, peroxiredoxins protect normal cells from oxidative damage that could promote oncogenesis (e.g., environmental stressors). In cancer, higher expression level of peroxiredoxins has been associated with both tumor growth and resistance to radiation therapies. However, this relationship between the expression of peroxiredoxins and the response to radiation is not evident from an analysis of data in The Cancer Genome Atlas (TCGA) or NCI60 panel of cancer cell lines. The focus of this review is to summarize the current experimental knowledge implicating this class of proteins in cancer, and to provide a perspective on the value of targeting peroxiredoxins in the management of cancer. Potential biases in the analysis of the TCGA data with respect to radiation resistance are also highlighted.

Personalized Genome-Scale Metabolic Models Identify Targets of Redox Metabolism in Radiation-Resistant Tumors

“…Furthermore, a larger differential response to ALDH1L1 knockdown was observed in 2 of the 3 radiationresistant cell lines, as predicted by FBA models. TCGA models accurately predicted that MTHFD1 knockdown would have a greater effect on GSH production in radiationsensitive cancers but greater effect on H 2 O 2 response in radiation-resistant cancers, suggesting that FBA models accurately capture other metabolic systems which impact ROS clearance besides glutathione-dependent pathways (Forshaw et al, 2019).…”

“…Ionizing radiation therapy results in the generation of reactive oxygen species (ROS) such as superoxide (O 2 -) and hydrogen peroxide (H 2 O 2 ), which oxidize the cellular environment and damage cellular structures including DNA (Brady et al, 2013;Cadet and Wagner, 2013;Reisz et al, 2014;Tominaga et al, 2004). Redox cofactors such as NADPH and GSH can be utilized by H 2 O 2 -scavenging enzymes to lower cellular levels of ROS (Forshaw et al, 2019;Harris et al, 2015). Additionally, these cofactors can directly promote DNA damage repair following oxidative damage, either by reduction of nitrogenous bases or utilization of NAD(P)H for nucleotide synthesis (Alvarez-Idaboy and Galano, 2012;Chatterjee, 2013;Franklin et al, 2016;Turgeon et al, 2018).…”

Proteomics of human glomerulonephritis by laser microdissection and liquid chromatography‐tandem mass spectrometry

“…Peroxiredoxin is an oxidoreductase present in cytoplasm of various cells, and its function is to protect cells from oxidative stress. 17,18 In an experimental mouse model of renal fibrosis, oxidative stress induced tubular atrophy and interstitial fibrosis were suppressed in the mice that overexpressed peroxiredoxin-1. 19 In humans, expression of peroxiredoxin-1 and peroxiredoxin-2 were increased in the podocytes of patients with advanced cases of diabetic nephropathy.…”

mTOR-Mediated Antioxidant Activation in Solid Tumor Radioresistance

“…However, in various solid tumors, because antioxidant mechanisms are activated at higher levels than in normal cells, tumor cells can be more tolerant to excessive ROS levels than normal cells [77]. NRF2-dependent antioxidant enzymes such as SOD, glutathione peroxidase (GPX), glutathione reductase (GSR), peroxiredoxin (PRX), and thioredoxin reductase (TXNRD) are upregulated in tumor cells, and high expression of these proteins is associated with poor prognosis in tumor patients (Table 1) [78][79][80][81][82][83]. Mitochondrial SOD2 was shown to be highly expressed in ovarian cancer patients and contribute to antitumor therapy resistance [84].…”