Abstract
Esophageal squamous cell carcinoma (ESCC) is a highly malignant cancer with poor response to both of chemotherapy and radiotherapy. 2-Acetylamino-3-[4-(2-acetylamino-2-carboxyethylsulfanylcarbonylamino) phenyl carbamoylsulfanyl] propionic acid (2-AAPA), an irreversible inhibitor of glutathione reductase (GR), is able to induce intracellular oxidative stress, and has shown anticancer activity in many cancer cell lines. In this study, we investigated the effects of 2-AAPA on the cell proliferation, cell cycle and apoptosis and aimed to explore its mechanism of action in human esophageal cancer TE-13 cells. It was found that 2-AAPA inhibited growth of ESCC cells in a dose-dependent manner and it did not deplete reduced glutathione (GSH), but significantly increased the oxidized form glutathione (GSSG), resulting in decreased GSH/GSSG ratio. In consequence, significant reactive oxygen species (ROS) production was observed. The flow cytometric analysis revealed that 2-AAPA inhibited growth of esophageal cancer cells through arresting cell cycle in G2/M phase, but apoptosis-independent mechanism. The G2/M arrest was partially contributed by down-regulation of protein expression of Cdc-25c and up-regulation of phosphorylated Cdc-2 (Tyr15), Cyclin B1 (Ser147) and p53. Meanwhile, 2-AAPA-induced thiol oxidative stress led to increased protein S-glutathionylation, which resulted in α-tubulin S-glutathionylation-dependent depolymerization of microtubule in the TE-13 cells. In conclusion, we identified that 2-AAPA as an effective thiol oxidative stress inducer and proliferation of TE-13 cells were suppressed by G2/M phase cell cycle arrest, mainly, through α-tubulin S-glutathionylation-mediated microtubule depolymerization. Our results may introduce new target and approach for esophageal cancer therapy through generation of GR-mediated thiol oxidative stress.
Highlights
Esophageal squamous cell carcinoma (ESCC), the predominant type of esophageal cancer in Asia [1, 2], is a malignancy associated with high mortality [3, 4]
2-AAPA-induced thiol oxidative stress led to increased protein S-glutathionylation, which resulted in α-tubulin Sglutathionylation-dependent depolymerization of microtubule in the TE-13 cells
Owing to its aggressive nature and poor response to chemotherapy and radiotherapy, adjuvant chemo- and radio-therapy have resulted in relieving symptoms and improving the life quality of patients with esophageal cancer, the overall 5-year survival rate for all patients with esophageal cancer is less than 20% [6,7,8], esophageal cancer still remains a challenging cancer disease to treat [9, 10]
Summary
Esophageal squamous cell carcinoma (ESCC), the predominant type of esophageal cancer in Asia [1, 2], is a malignancy associated with high mortality [3, 4]. Induction of oxidative stress and production of ROS are known to increase the rate of mutations in the cells [11]. Cancer cells have a higher level of oxidative stress than non-malignant cells, they are vulnerable to the acute induction of oxidative stress caused by agents inducing ROS [11]. ROS can exert signaling functions by modulating, at different layers, protein oxidation since proteins have “cysteine switches” that can be reversibly reduced or oxidized, supporting the dynamic signaling regulation function. In this scenario, S-glutathionylation is a posttranslational modification involved in oxidative cellular response [17]. The present studies were aimed to explore the effects of 2-AAPA on proliferation of TE-13 cells and the possible mechanism of act in 2-AAPA-induced G2/M phase cell cycle arrest
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