Abstract
FUS1/TUSC2 is a mitochondrial tumor suppressor with activity to regulate cellular oxidative stress by maintaining balanced ROS production and mitochondrial homeostasis. Fus1 expression is inhibited by ROS, suggesting that individuals with a high level of ROS may have lower Fus1 in normal tissues and, thus, may be more prone to oxidative stress-induced side effects of cancer treatment, including radiotherapy. As the role of Fus1 in the modulation of cellular radiosensitivity is unknown, we set out to determine molecular mechanisms of Fus1 involvement in the IR response in normal tissues. Mouse whole-body irradiation methodology was employed to determine the role for Fus1 in the radiation response and explore underlying molecular mechanisms. Fus1−/− mice were more susceptible to radiation compared with Fus1+/+ mice, exhibiting increased mortality and accelerated apoptosis of the GI crypt epithelial cells. Following untimely reentrance into the cell cycle, the Fus1−/− GI crypt cells died at accelerated rate via mitotic catastrophe that resulted in diminished and/or delayed crypt regeneration after irradiation. At the molecular level, dysregulated dynamics of activation of main IR response proteins (p53, NFκB, and GSK-3β), as well as key signaling pathways involved in oxidative stress response (SOD2, PRDX1, and cytochrome c), apoptosis (BAX and PARP1), cell cycle (Cyclins B1 and D1), and DNA repair (γH2AX) were found in Fus1−/− cells after irradiation. Increased radiosensitivity of other tissues, such as immune cells and hair follicles was also detected in Fus1−/− mice. Our findings demonstrate a previously unknown radioprotective function of the mitochondrial tumor suppressor Fus1 in normal tissues and suggest new individualized therapeutic approaches based on Fus1 expression.
Highlights
About 50% of current cancer patients receive ionizing radiation (IR) therapy.[1]
We previously found that deficiency of mitochondrial tumor suppressor Fus[1] results in multiple immune system defects, perturbed inflammatory response, aberrant cytokine expression, as well as dysregulation of mitochondrial homeostasis including generation of high levels of reactive oxygen species (ROS).[15,16]
We demonstrated that whole-body irradiation (WBI) of Fus[1] À / À mice resulted in increased and accelerated death likely driven by accelerated apoptosis and untimely reentry into cell cycle, leading to mitotic catastrophe of crypt epithelial cells and diminished crypt regeneration
Summary
About 50% of current cancer patients receive ionizing radiation (IR) therapy.[1]. tumors can develop or have intrinsic radioresistance, the primary limitation of radiation therapy is tolerance of normal tissues. We previously found that deficiency of mitochondrial tumor suppressor Fus[1] results in multiple immune system defects, perturbed inflammatory response, aberrant cytokine expression, as well as dysregulation of mitochondrial homeostasis including generation of high levels of ROS.[15,16] Fus[1] expression is epigenetically suppressed by asbestos exposure[17,16] and tobacco smoking,[18,19] demonstrating that inhibition of Fus[1] expression can occur in normal tissues under chronic oxidative stress These findings suggest that individuals with chronic oxidative stress may have low Fus[1] levels and become more sensitive to the side effects of radiation therapy. Received 26.2.13; revised 02.5.13; accepted 10.5.13; Edited by G Raschellamore sensitive to IR therapy.[17,18,19] Fus[1] may have an important role in the regulation of cellular radiosensitivity/ radioresistance in normal and tumor tissues as well as be a prospective target for therapies that better balance risks and benefits of radiation treatment of tumors
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