Nuclear factor E2-related factor 2 Dependent Overexpression of Sulfiredoxin and Peroxiredoxin III in Human Lung Cancer

Abstract

Background/AimsOxidative stress results in protein oxidation and is implicated in carcinogenesis. Sulfiredoxin (Srx) is responsible for the enzymatic reversal of inactivated peroxiredoxin (Prx). Nuclear factor E2-related factor 2 (Nrf2) binds to antioxidant responsive elements and upregulates the expression of Srx and Prx during oxidative stress. We aimed to elucidate the biological functions and potential roles of Srx in lung cancer.MethodsTo study the roles of Srx and Prx III in lung cancer, we compared the protein levels of Nrf2, Prxs, thioredoxin, and Srx in 40 surgically resected human lung cancer tissues using immunoblot and immunohistochemical analyses. Transforming growth factor-β1, tumor necrosis factor-α, and camptothecin treatment were used to examine Prx III inactivation in Mv1Lu mink lung epithelial cells and A549 lung cancer cells.ResultsPrx I and Prx III proteins were markedly overexpressed in lung cancer tissues. A significant increase in the oxidized form of a cysteine sulfhydryl at the catalytic site of Prxs was found in carcinogenic lung tissue compared to normal lung tissue. Densitometric analyses of immunoblot data revealed significant Srx expression, which was higher in squamous cell carcinoma tissue (60%, 12/20) than in adenocarcinoma (20%, 4/20). Also, Nrf2 was present in the nuclear compartment of cancer cells.ConclusionsSrx and Prx III proteins were markedly overexpressed in human squamous cell carcinoma, suggesting that these proteins may play a protective role against oxidative injury and compensate for the high rate of mitochondrial metabolism in lung cancer.

Sulfiredoxin inhibitor induces preferential death of cancer cells through reactive oxygen species-mediated mitochondrial damage

“…The initial correlation of Srx to cancer emerged from its differential expression in the transformation-sensitive mouse JB6 epidermal cells [36]. It was further demonstrated that Srx is overexpressed in cancers of skin, lung, and rectum, but not in normal tissues, and has an oncogenic role in promoter-induced tumorigenesis of skin and colon, and in lung cancer cells [24][25][26]37,38], indicating that Srx might be targeted for cancer prevention or treatment. Here, we showed that the inhibition of Srx activity in human lung adenocarcinoma A549 cells causes oxidative stress, which in turn leads to mitochondrial damage resulting in apoptotic cell death.…”

“…Recent findings have shown that Srx is induced by a variety of stimuli or chemicals that result in oxidative damage in Srx-deficient cells [21,22]. It was reported that an enhanced level of Srx promotes cell proliferation [23], and Srx is highly expressed in several human tumors including skin tumors, rectal carcinoma and lung adenocarcinoma, compared with the levels found in corresponding normal tissues [24,25]. Srx was also found to be required for anchorage-independent colony formation by human lung cancer cells and for cell migration and invasion in vitro, as well as for the formation of metastases by these cells in vivo [26].…”

Role of sulfiredoxin as a regulator of peroxiredoxin function and regulation of its expression

“…Knockdown of Srx also impaired c-Jun phosphorylation and markedly attenuated AP-1-dependent luciferase reporter activity, suggesting that Srx functions as a positive regulator of c-Jun activation in addition to being a target of AP-1 activation. Screening of human tissue by microarray analysis revealed the level of Srx expression to be increased in tumors, including those of the skin, lung, and rectum, compared with that in corresponding normal tissue [41,49]. Srx was also found to be required for anchorage-independent colony formation by human lung cancer cells and for cell migration and invasion in vitro, as well as for the formation of metastases by these cells in vivo [50].…”

The sulfiredoxin–peroxiredoxin (Srx–Prx) axis in cell signal transduction and cancer development

“…It may also enhance cell migration in lung cancer in a Prx-independent manner by interacting with S100A4 ( a calcium binding protein ) and non-muscle myosin IIA (NMIIA) [49]. Aberrant expression of Srx in lung squamous cell carcinoma, lung adenocarcinoma, and pancreatic cancer is correlated with poor survival in those patients [71; 72; 73]. Srx protein is also over-expressed in renal cell carcinoma where it is proposed to be a good antibody target that can result in tumor cell death [74].…”