Sulfiredoxin–Peroxiredoxin IV axis promotes human lung cancer progression through modulation of specific phosphokinase signaling

Abstract

Oxidative stress is known to cause tumorigenesis through induction of DNA and lipid damage. It also promotes cancer progression through a largely unknown mechanism. Sulfiredoxin (Srx) is a novel oxidative stress-induced antioxidant protein whose function in tumorigenesis and cancer progression has not been well studied. We report that Srx is highly expressed in human lung cancer. Knockdown of Srx reduces anchorage-independent colony formation, cell migration, and invasion of human lung cancer cells. Srx preferentially interacts with Peroxiredoxin (Prx) IV relative to other Prxs due to its intrinsic higher binding affinity. Knockdown of Prx IV recapitulates the phenotypic changes of depleting Srx. Disruption or enhancement of the Srx-Prx IV axis leads respectively to reduction or acceleration of tumor growth and metastasis formation in vivo. Through identification and validation of the downstream mediators we unraveled the Srx-mediated signaling network that traverses AP-1-activating and other phosphokinase signaling cascades. Our work reveals that the Srx-Prx IV axis is critical for lung cancer maintenance and metastasis, suggesting that targeting the Srx-Prx IV axis may provide unique effective strategies for cancer prevention and treatment.oncogene | signal transduction L ung cancer is the most common form of human cancer and is the leading cause of cancer mortality worldwide. Despite recent progress in early detection and combined therapeutic strategies, the overall survival rate of patients has not been significantly improved (1). Many risk factors, including the exposure to tobacco smoke, have been identified as causally related to lung carcinogenesis in patients. Tobacco smoke contains a number of carcinogens, and metabolism of these carcinogens generates active metabolites directly leading to formation of DNA adducts and the accumulation of oxygen-free radicals that induce oxidative stress that contributes significantly to tumorigenesis and cancer progression (2).Oxygen-free radicals, including reactive oxygen species (ROS) and reactive nitrogen species, have been shown to be causally related to cancer progression and metastasis. However, the molecular mechanisms of oxidative stress in cancer maintenance and metastases formation are still not well understood, due in part to the dual roles of ROS as both deleterious and beneficial species in cancer cells. Under physiological conditions ROSinduced oxidative stress response causes cellular senescence and apoptosis. Cancer cells have an enhanced defense system characterized by intrinsically higher expression of antioxidant proteins, and ROS are more likely to function as mediators of intracellular signaling cascades that are critical for maintenance of tumor phenotypes (3). Sulfiredoxin (Srx), or neoplastic progression 3, was previously identified as a differentially expressed gene with unknown function that distinguished transformed and transformation-sensitive from transformation-resistant mouse epidermal cells (4). More recent studies substantiate that Srx...

Peroxiredoxins, gerontogenes linking aging to genome instability and cancer

“…Interestingly, modified (presumably oxidized) PrdxI accumulates in human lung cancer samples (Park et al 2006), indicating, perhaps, a role for the chaperone function of PrdxI in tumorigenesis (or elevated peroxide signaling). Furthermore, a recent study reported that increased Srx expression deregulates PrdxIV activity in lung cancers, and Srx and PrdxIV were found to be required for several key aspects of tumor growth and metastasis; e.g., anchorage-dependent colony formation, cell migration, and invasion (Wei et al 2011). In a previous study, increased Srx expression was observed also in several types of skin cancers (Wei et al 2008), indicating that deregulation of Prx activity may be involved in several types of human cancers.…”

Loss of SPARC in bladder cancer enhances carcinogenesis and progression

“…We also detected increased 8-OHdG, suggestive of oxidative-and inflammationmediated DNA damage, in bladders of BBN-treated Sparc -/-mice compared with the Sparc +/+ ( Figure 4B). Because ROS results in lipid peroxidation and oxidation of proteins that contribute to carcinogenesis via activation of oncogenic transcription factors such as NF-κB and AP-1 (34,35), we determined the levels of lipid peroxidation product 8-isoprostane and found higher levels in Sparc -/-mice compared with their wild-type counterparts ( Figure 4C). Moreover, markers of protein oxidation, sulfiredoxin, and nicotinamide N-methyl transferase (NNMT) were significantly increased in bladder tumor tissues of Sparc -/-mice ( Figure 4D).…”

“…Moreover, markers of protein oxidation, sulfiredoxin, and nicotinamide N-methyl transferase (NNMT) were significantly increased in bladder tumor tissues of Sparc -/-mice ( Figure 4D). Both have been correlated with progression and invasiveness of many cancers, including bladder (34,36).…”

“…NF-κB and AP-1 (34,35,37). Higher levels of ROS in Sparc -/-urothelia prompted us to evaluate potential downstream signaling pathways.…”

Peroxiredoxin 4 (PRDX4): Its Critical <em>In Vivo</em> Roles in Animal Models of Metabolic Syndrome Using Our Unique PRDX4 Transgenic Mice

“…can also cause carcinogenesis through the induction of DNA damage and lipid dysregulation [86][87][88]. Indeed, the PRDX4 expression is variably high in most human malignant neoplasms, including prostate/lung adenocarcinoma or glioblastoma, and surprisingly, the suppression of PRDX4 leads to a significant reduction in tumor growth and/or metastatic potential [88][89][90][91][92][93]. In line with those findings, our data from clinical samples [10] show that patients with type 2 DM have significantly higher serum hPRDX4 levels than healthy adult volunteers, likely due to the greater demand for antioxidant defense in this chronic inflammatory disease.…”