Interplay Between Mitochondrial Peroxiredoxins and ROS in Cancer Development and Progression

Abstract

Mitochondria are multifunctional cellular organelles that are major producers of reactive oxygen species (ROS) in eukaryotes; to maintain the redox balance, they are supplemented with different ROS scavengers, including mitochondrial peroxiredoxins (Prdxs). Mitochondrial Prdxs have physiological and pathological significance and are associated with the initiation and progression of various cancer types. In this review, we have focused on signaling involving ROS and mitochondrial Prdxs that is associated with cancer development and progression. An upregulated expression of Prdx3 and Prdx5 has been reported in different cancer types, such as breast, ovarian, endometrial, and lung cancers, as well as in Hodgkin's lymphoma and hepatocellular carcinoma. The expression of Prdx3 and Prdx5 in different types of malignancies involves their association with different factors, such as transcription factors, micro RNAs, tumor suppressors, response elements, and oncogenic genes. The microenvironment of mitochondrial Prdxs plays an important role in cancer development, as cancerous cells are equipped with a high level of antioxidants to overcome excessive ROS production. However, an increased production of Prdx3 and Prdx5 is associated with the development of chemoresistance in certain types of cancers and it leads to further complications in cancer treatment. Understanding the interplay between mitochondrial Prdxs and ROS in carcinogenesis can be useful in the development of anticancer drugs with better proficiency and decreased resistance. However, more targeted studies are required for exploring the tumor microenvironment in association with mitochondrial Prdxs to improve the existing cancer therapies and drug development.

Keywords: ROS scavengers; mitochondria; peroxiredoxins; reactive oxygen species; tumorigenesis.

Figure 1

Mitochondrial reactive oxygen species (ROS) scavengers and cancer development. Eukaryotic cells depend upon the mitochondria for energy production, and reactive oxygen species (ROS) are produced as byproducts during adenosine triphosphate (ATP) generation by the mitochondria. The amount of mitochondrial ROS is balanced by ROS scavengers in the mitochondria of normal eukaryotic cells and these ROS regulate different cellular processes such as cell proliferation and differentiation by acting as signaling molecules. The loss of this specific balance between ROS and ROS scavengers leads to an outburst growth of cells, resulting in cancer initiation and development.

Figure 2

Structural comparison of mitochondrial peroxiredoxins (Prdxs). Peroxiredoxin 3 (Prdx3) and Peroxiredoxin 5 (Prdx5) contain a mitochondrial targeting sequence (MTS) at their amino terminal (N-terminal) and this enables them to reside in the mitochondria. Prdx5 in addition to MTS also contains a peroxisomal targeting sequence (PTS) at its carboxyl terminal (C-terminal) that is responsible for the entry of Prdx5 in the peroxisomes. Both mitochondrial Prdxs comprise peroxidatic cysteine (Cp) and resolving cysteine (Cr) which play an essential role in their catalytic mechanisms. In Prdx3, Cp is located at residue 47, whereas, in Prdx5, it is located at residue 48 [35].

Figure 3

Role of antioxidants in cancerous cells. Mutations in mitochondria and mitochondrial dysfunctions lead to the production of increased amount of ROS by the activation of c-Myc and K-ras factors. The increased production of ROS leads to an imbalance between ROS and its scavengers. This imbalance activates a number of signaling pathways such as PI3K and mitogen-activated protein kinase (MAPK), resulting in tumor initiation and progression. The increased amount of ROS in cancerous cells requires an upregulated expression of antioxidants to prevent cell death. Thus, the activation of certain transcription factors (NRF2 and FOXO) and tumor suppressors (p53) induces the upregulation of mitochondrial Prdxs to compensate the increased production of ROS. Thus, mitochondrial Prdxs along with other scavengers act to protect the cancerous cells from ROS-mediated cell death.

Figure 4

Microenvironment of mitochondrial Prdxs in cancer. The involvement of mitochondrial Prdxs in cancer depends on their interaction with different factors including transcription factors, different response elements, micro RNAs, and cancer-related genes. The microenvironment of Prdx3 involves its regulation by various transcription factors such as FOXO family transcription factors, Jun-D, and TIMP1 in colon, prostate, and hepatocellular carcinomas. These factors are associated with the upregulation of Prdx3 in the cancerous cells for the abovementioned cancer types. Prdx3 interacts with miR-383 and miR-23b in medulloblastoma and prostate cancer, further regulated by c-Myc in breast cancer and hypoxia-inducible factors in renal cell carcinoma. Similarly, the expression of Prdx5 in different malignancies depends on its regulation by a variety of interacting partners such as c-Myc and GATA1 in breast cancer, Snail in gastric cancer, and Ets1/2 and HMGB1 in prostate cancer. Additionally, Prdx5 interacts with transcription factors AP-1 and NF-κB, insulin and glucocorticoid response elements for the initiation of tumorigenesis and tumor progression.

Figure 5

Mitochondrial Prdxs in development of Chemoresistance. The upregulated expression of mitochondrial Prdxs is associated with the development of drug resistance in a number of cancer types leading to complications in cancer treatment. These upregulated Prdxs can be specifically targeted in cancerous cells to develop new drugs against cancer with better efficacy and without causing any harm to the normal cells.