Peroxiredoxin-6 regulates p38-mediated epithelial–mesenchymal transition in HCT116 colon cancer cells

Reactive oxygen species (ROS), including hydrogen peroxide (H2O2), are highly reactive and can cause oxidative stress during cellular metabolism [1]. Therefore, ROS regulation is essential for healthy cellular metabolism, for which, most cells possess superoxide dismutase, catalase, and peroxiredoxin. The redox balance is known for maintaining the balance between ROS and antioxidant enzymes [2]. It is supported by the capacity of the antioxidant defense system in cellular metabolism [3]. At an optimum level, ROS, underregulated by antioxidant enzymes, functions as a mediator of cell growth [4], metabolism [5], signal messenger [6], and maintaining redox balance [7]. If ROS overwhelms the capacity of the cellular antioxidant defense system, excessive oxidative stress would destroy DNA, lipids, and proteins [8]. It promotes abnormal cell growth and proliferation, in case ROS level is out of control due to antioxidants. Compared with normal cells, oxidative stress is highly increased in cancer cells because of excessive ROS generation [9]. Furthermore, this enhanced oxidative stress can lead to tumor cell growth and metastasis [10]. Therefore, the regulation of antioxidants is closely related to cancer cell growth and proliferation.

Peroxiredoxins (Prxs) are powerful antioxidant enzymes that remove hydroperoxide, known as intracellular ROS [11]. The Prxs have six isoforms and are divided into three types by their structure and reduction processes, i.e., typical-2-Cys, atypical-2-Cys and atypical-1-Cys. Prx1, 2, 3, and 4 are typical-2-Cys Prx, and Prx5 is an atypical-2-Cys Prx. In contrast, 2-Cys Prx uses thioredoxin for its reduction, whereas Prx6, a 1-Cys Prx, is the only Prx that uses glutathione for the same process [12]. Like other Prxs series, many studies regarding Prx6 and diseases induced by oxidative stress have already been done. Moreover, studies have reported that Prx6 makes cancer cells sensitive in chemotherapy, resulting in apoptosis [13]. However, compared with other cancers, there are not many studies that have evaluated the roles of Prx6 in colon cancer development. Therefore, it is necessary to study the function and mechanism of Prx6 in the proliferation and growth of colorectal cancer.

The epithelial–mesenchymal transition (EMT) is described as a process in which the less motility epithelial cells are transformed into mesenchymal cells that gain motility [14]. The EMT can be found in embryonic development [15], fibrosis of tissues [16], and metastasis of cancer [17]. Studies have demonstrated that EMT is associated with cancer progression and metastasis. For the EMT to occur in cancer cells, genes, such as Snai1, Twist1, and Zeb1, need to be expressed [18]. Furthermore, epithelial marker proteins, such as E-cadherin, occludin, and type-4 collagen are decreased in cancer cells when EMT occurs [19]. These factors result in more invasive and metastatic cancer cells, thereby making cancer therapies difficult. In contrast, gene transcription factors of EMT (Snai1, Twist1, and Zeb1) affect the epithelial features of the cells. Also, they induce an increase in mesenchymal features. Therefore, the regulation of EMT signaling through modulation of transcription factors is a critical alleviation factor of cancer progression and metastasis.

The mitogen-activated protein kinases (MAPKs) are specific for serine and threonine involved in various cellular responses, i.e., proliferation, gene expression, and cell survival. In mammalian cells, MAPKs are primarily defined into three subgroups: the extracellular signal-regulated kinases (ERKs, including ERK-1 and ERK-2), the c-Jun N-terminal kinases (JNKs, including JNK-1, JNK-2, and JNK-3), and the p38 MAPKs (including p38-α, p38-β, p38-γ, and p38-δ). The MAPK activation is stimulated by proinflammatory cytokines [20], heat shock [21], and oxidative stress [22]. As one of the well-known MAPK stimulators, ROS activates them, serving as the cellular second messenger that enables the well-controlled proliferation and growth of cells [6]. However, excessive ROS inhibits cell growth and proliferation with MAPKs, leading to apoptosis [23]. Furthermore, among the MAPKs pathway, the p38 pathway plays an essential role in inhibiting EMT [24]. By maintaining E-cadherin through tak1-NF-κb signaling, p38 inhibits EMT. Therefore, the p38 pathway regulation through the ROS-level modulation is a fascinating research avenue for cancer therapy studies.

Therefore, Prx6 is a powerful antioxidant enzyme used for cancer therapy through ROS regulation. However, in the case of colon cancer, the capacity of Prx6 to regulate EMT signaling in colon cancer cell is still unknown. Therefore, in this study, we investigated the relationship between ROS regulation by Prx6 and EMT in colon cancer cells.

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