Abstract
The excessive and inappropriate production of reactive oxygen species (ROS) can cause oxidative stress and is implicated in the pathogenesis of lung cancer. Cyclophilin A (CypA), a member of the immunophilin family, is secreted in response to ROS. To determine the role of CypA in oxidative stress injury, we investigated the role that CypA plays in human lung carcinoma (A549) cells. Here, we showed the protective effect of human recombinant CypA (hCypA) on hydrogen peroxide (H2O2)-induced oxidative damage in A549 cells, which play crucial roles in lung cancer. Our results demonstrated that hCypA substantially promoted cell viability, superoxide dismutase (SOD), glutathione (GSH), and GSH peroxidase (GSH-Px) activities, and attenuated ROS and malondialdehyde (MDA) production in H2O2-induced A549 cells. Compared with H2O2-induced A549 cells, Caspase-3 activity in hCypA-treated cells was significantly reduced. Using Western blotting, we showed that hCypA facilitated Bcl-2 expression and inhibited Bax, Caspase-3, Caspase-7, and PARP-1 expression. Furthermore, hCypA activates the PI3K/Akt/mTOR pathway in A549 cells in response to H2O2 stimulation. Additionally, peptidyl-prolyl isomerase activity was required for PI3K/Akt activation by CypA. The present study showed that CypA protected A549 cells from H2O2-induced oxidative injury and apoptosis by activating the PI3K/Akt/mTOR pathway. Thus, CypA might be a potential target for lung cancer therapy.
Highlights
Chronic enhanced oxidative stress is a pathogenic feature of most chronic diseases, such as cancer and diabetes, as well as pulmonary, cardiovascular, kidney, and neurodegenerative diseases [1,2]
To investigate whether Cyclophilin A (CypA) can be induced by hydrogen peroxide (H2O2) stimulation, quantitative real-time PCR analysis was done using mRNA extracted from the human lung carcinoma (A549) cell line exposed to H2O2 for the indicated periods of time
To detect the cytotoxicity effect of human recombinant CypA on A549 cells, A549 cells were treated with hCypA at different concentrations ranging from 100 to 1000 ng/ml for 24 h
Summary
Chronic enhanced oxidative stress is a pathogenic feature of most chronic diseases, such as cancer and diabetes, as well as pulmonary, cardiovascular, kidney, and neurodegenerative diseases [1,2]. Oxidative stress usually arise from the excessive accumulation of reactive oxygen species (ROS), which include hydrogen peroxide (H2O2), superoxide anions, hydroxyl radicals, and singlet oxygen [3]. Elevated levels of ROS-induced oxidative stress can induce cancer cell death [4,5,6]. To prevent excessive intracellular ROS, cancer cells have been found to maintain a redox balance by increasing their antioxidant potential [7,8,9]. CypA regulates multiple cellular functions, including protein folding, cell signaling, inflammation, tumorigenesis, and antiviral immunity [13,14,15,16,17]. CypA is secreted by VSMCs in response to oxidative stress and mediates
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