Interaction between mitochondrial related anti-oxidant genes, and cancer cells apoptosis induction by ELF-EMFs
Interaction between mitochondrial related anti-oxidant genes, and cancer cells apoptosis induction by ELF-EMFs
Mohadeseh Shayeghan,1Alireza Madjid Ansari,2Flora Forouzesh,3Mohammad Amin Javidi,4,*
1. Integrative Oncology Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran 2. Integrative Oncology Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran 3. Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran 4. Integrative Oncology Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran
Introduction: Extremely Low-Frequency Electromagnetic Fields (ELF-EMFs) with frequencies from 0 Hz to 300 Hz which are classified as the non-ionizing radiation of the electromagnetic spectrum are not too strong to damage DNA or to induce thermal effects on tissue. On the other hand, ELF-EMFs can specifically inhibit cancer cell proliferation in vitro and in vivo; this may depict a bright promising future as a cancer treatment candidate. In this regard, different underlying mechanisms of action have been proposed for this anti-cancer effect. Recently, it has been stated that ELF-EMFs affect apoptosis-related molecular pathways through increasing reactive oxygen species (ROS) levels and changing the balance between ROS and the antioxidant system (oxidative stress) which modulate cell fate and orchestrate apoptosis. However, the exact source of ROS elevation induced by ELF-EMFs in cancer cells is not transparent. In this area, mitochondria, one of the major resources of ROS production, can be considered as the main mechanism in increasing ROS levels by ELF-EMFs and consequently apoptosis induction. Hence, the aim of this study is to review the impact of ELF-EMFs on the mitochondria and affected underlying pathways in different types of cancer cells.
Methods: Related articles were selected from databases like PubMed, Scopus, ScienceDirect, and Google Scholar with the following keywords: ELF-EMF, mitochondria, anticancer, ROS, apoptosis, and proliferation.
Results: Exposure to ELF-EMFs could up-regulate the MAPK signaling pathway which promotes the expression level of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PPARGC1A, also known as PGC-1α). PGC-1α plays a key role in oxidative metabolism which can enhance mitochondrial biogenesis and mitochondrial respiratory chain activity. Also, PGC-1α activates a transcription factor called nuclear factor E2-related factor 2 (Nrf2). Increased ROS level by mitochondrial respiratory chain and imbalance between ROS and ROS scavengers, antioxidant enzymes, leads to activation of Nrf2 which binds to the antioxidant response elements and promotes expression level of antioxidant enzymes such as catalases, superoxide dismutases (SODs), and glutathione peroxidases to balance redox status. On the other hand, ELF-EMFs exposure could induce sirtuin-3 (SIRT-3) expression level, the regulator of antioxidant machinery and mitochondrial oxidative responses. Overexpression of SIRT-3 increases the expression level of mitochondrial SOD (SOD2) and catalase in favor of maintaining redox balance. In addition, SIRT-3 reduces ROS levels by deacetylating forkhead box O 3a (FoxO3a), a transcription factor that increases the level of SOD2 and catalase.
Conclusion: As mentioned above, the accumulation of intracellular ROS levels and cellular oxidative stress can promote the expression level of PGC-1α to maintain redox balance by increasing the level of ROS scavengers. Hence, during oxidative stress in cancer cells, PGC-1α has an important role in cellular adaptation and reprogramming which leads to cancer cell proliferation and survival. Also, the promoted expression level of PGC-1α is related to metastasis and poor prognosis in patients with cancer. In this case, PGC-1α silencing leads to mitochondrial dysfunction which can reduce the viability and invasion of tumor cells and can induce apoptosis through mitochondrial apoptotic pathways. In addition, SIRT-3 can either affects the quality of function or the quantity of mitochondria. Knockdown of this mitochondrial deacetylase brings out mitochondrial dysfunction and reduces cancer cell viability. Thus, PGC-1α and SIRT-3 genes silencing become one of the therapeutic targets in cancer treatment programs. Also, reactive oxygen species molecules take part in various intracellular signaling pathways and it is demonstrated that ELF-EMFs influence multiple signaling cascades in exposed cells by means of ROS perturbation in favor of apoptosis activation processes. So, using these fields in association with PGC-1α and SIRT-3 silencing could be effective in cancer treatment.