Abstract
Prolonged oxidative stress favors tumorigenic environment and inflammation. Oxidative stress may trigger redox adaptation mechanism(s) in tumor cells but not normal cells. This may increase levels of intracellular antioxidants and establish a new redox homeostasis. Nrf-2, a master regulator of battery of antioxidant genes is constitutively activated in many tumor cells. Here we show that, murine T cell lymphoma EL-4 cells show constitutive and inducible radioresistance via activation of Nrf-2/ERK pathway. EL-4 cells contained lower levels of ROS than their normal counterpart murine splenic lymphocytes. In response to radiation, the thiol redox circuits, GSH and thioredoxin were modified in EL-4 cells. Pharmacological inhibitors of ERK and Nrf-2 significantly enhanced radiosensitivity and reduced clonogenic potential of EL-4 cells. Unirradiated lymphoma cells showed nuclear accumulation of Nrf-2, upregulation of its dependent genes and protein levels. Interestingly, MEK inhibitor abrogated its nuclear translocation suggesting role of ERK in basal and radiation induced Nrf-2 activation in tumor cells. Double knockdown of ERK and Nrf-2 resulted in higher sensitivity to radiation induced cell death as compared to individual knockdown cells. Importantly, NF-kB which is reported to be constitutively active in many tumors was not present at basal levels in EL-4 cells and its inhibition did not influence radiosensitivity of EL-4 cells. Thus our results reveal that, tumor cells which are subjected to heightened oxidative stress employ master regulator cellular redox homeostasis Nrf-2 for prevention of radiation induced cell death. Our study reveals the molecular basis of tumor radioresistance and highlights role of Nrf-2 and ERK.
Highlights
Radiation therapy is an integral component of treatment of different types of solid cancers
Murine T cell Lymphoma Cells have Active Redox Circuits Basal and ionizing radiation induced levels of GSH were estimated in normal lymphocytes and lymphoma cells by conventional enzyme cycling method
Inhibitors of Extracellular Related Kinase (ERK), nuclear factor erythroid-2 related factor-2 (Nrf-2), HO-1 and thioredoxin reductase significantly enhanced radiation induced cell death in EL-4 cells suggesting their potential role in cellular radioresistance (Fig. 3A&B)
Summary
Radiation therapy is an integral component of treatment of different types of solid cancers. Improved understanding of causes for constitutive and induced radioresistance in tumor cells may pave the way for designing effective treatment modality. Ionizing radiation causes both direct and indirect damage to cells. Generation of ROS creates oxidative stress and disturbs redox balance within the cells [2] Due to their high reactivity, electrophilicity and short lived nature they react with critical biomolecules in cell such as lipids, proteins and DNA [3]. This damage if unrepaired irreversibly commits cells to undergo apoptosis [4]. We have shown that GSH levels and antioxidant enzyme activities were higher in lymphoma cells as compared to normal lymphocytes [4]
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