Ionizing Radiation Upregulates Glutamine Metabolism and Induces Cell Death via Accumulation of Reactive Oxygen Species

Glutamine metabolism provides energy to tumor cells and also produces reactive oxygen species (ROS). Excessive accumulation of ROS can damage mitochondria and eventually lead to cell death. xCT (SLC7A11) is responsible for the synthesis of glutathione in order to neutralize ROS. In addition, mitophagy can remove damaged mitochondria to keep the cell alive. Ionizing radiation kills tumor cells by causing the accumulation of ROS, which subsequently induces nuclear DNA damage. With this in mind, we explored the mechanism of intracellular ROS accumulation induced by ionizing radiation and hypothesized new methods to enhance the effect of radiotherapy. We used MCF-7 breast cancer cells and HCT116 colorectal cancer cells in our study. The above-mentioned cells were irradiated with different doses of X-rays or carbon ions. Clone formation assays were used to detect cell proliferation, enzyme-linked immunosorbent assay (ELISA) detected ATP, and glutathione (GSH) production, while the expression of proteins was detected by Western blot and quantitative real-time PCR analysis. The production of ROS was detected by flow cytometry, and immunofluorescence was used to track mitophagy-related processes. Finally, BALB/C tumor-bearing nude mice were irradiated with X-rays in order to further explore the protein expression found in tumors with the use of immunohistochemistry. Ionizing radiation increased the protein expressions of ASCT2, GLS, and GLUD in order to upregulate the glutamine metabolic flux in tumor cells. This caused an increase in ATP secretion. Meanwhile, ionizing radiation inhibited the expression of the xCT (SLC7A11) protein and reduced the generation of glutathione, leading to excessive accumulation of intracellular ROS. The mitophagy inhibitor, or knockdown Parkin gene, is able to enhance the ionizing radiation-induced ROS production and increase nucleus DNA damage. This combined treatment can significantly improve the killing effect of radiation on tumor cells. We concluded that ionizing radiation could upregulate the glutamine metabolic flux and enhance ROS accumulation in mitochondria. Ionizing radiation also decreased the SLC7A11 expression, resulting in reduced GSH generation. Therefore, inhibition of mitophagy can increase ionizing radiation-induced cell death.

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Involvement of ERK-Nrf-2 Signaling in Ionizing Radiation Induced Cell Death in Normal and Tumor Cells

PLoS ONE ◽

10.1371/journal.pone.0065929 ◽

2013 ◽

Vol 8 (6) ◽

pp. e65929 ◽

Cited By ~ 21

Author(s):

Raghavendra S. Patwardhan ◽

Rahul Checker ◽

Deepak Sharma ◽

Santosh K. Sandur ◽

Krishna B. Sainis

Keyword(s):

Cell Death ◽

Ionizing Radiation ◽

Tumor Cells ◽

Radiation Induced

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Differential Effects of Gold Nanoparticles and Ionizing Radiation on Cell Motility between Primary Human Colonic and Melanocytic Cells and Their Cancerous Counterparts

International Journal of Molecular Sciences ◽

10.3390/ijms22031418 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1418

Author(s):

Elham Shahhoseini ◽

Masao Nakayama ◽

Terrence J. Piva ◽

Moshi Geso

Keyword(s):

Gold Nanoparticles ◽

Ionizing Radiation ◽

Cancer Cells ◽

Cell Lines ◽

Colorectal Adenocarcinoma ◽

X Rays ◽

Cell Adherence ◽

Cancerous Cell ◽

Primary Colon ◽

Radiation Induced

This study examined the effects of gold nanoparticles (AuNPs) and/or ionizing radiation (IR) on the viability and motility of human primary colon epithelial (CCD841) and colorectal adenocarcinoma (SW48) cells as well as human primary epidermal melanocytes (HEM) and melanoma (MM418-C1) cells. AuNPs up to 4 mM had no effect on the viability of these cell lines. The viability of the cancer cells was ~60% following exposure to 5 Gy. Exposure to 5 Gy X-rays or 1 mM AuNPs showed the migration of the cancer cells ~85% that of untreated controls, while co-treatment with AuNPs and IR decreased migration to ~60%. In the non-cancerous cell lines gap closure was enhanced by ~15% following 1 mM AuNPs or 5 Gy treatment, while for co-treatment it was ~22% greater than that for the untreated controls. AuNPs had no effect on cell re-adhesion, while IR enhanced only the re-adhesion of the cancer cell lines but not their non-cancerous counterparts. The addition of AuNPs did not enhance cell adherence. This different reaction to AuNPs and IR in the cancer and normal cells can be attributed to radiation-induced adhesiveness and metabolic differences between tumour cells and their non-cancerous counterparts.

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Three-dimensional cell organization leads to a different type of ionizing radiation-induced cell death: MG-63 monolayer cells undergo mitotic catastrophe while spheroids die of apoptosis

International Journal of Oncology ◽

10.3892/ijo.31.6.1473 ◽

2007 ◽

Author(s):

Paola Indovina ◽

Gabriella Rainaldi ◽

Maria Santini

Keyword(s):

Cell Death ◽

Ionizing Radiation ◽

Three Dimensional ◽

Mitotic Catastrophe ◽

Cell Organization ◽

Radiation Induced ◽

Dimensional Cell

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Inhibition of Rac1 attenuates radiation-induced lung injury while suppresses lung tumor in mice

Cell Death Discovery ◽

10.1038/s41420-021-00791-8 ◽

2022 ◽

Vol 8 (1) ◽

Author(s):

Ni An ◽

Zhenjie Li ◽

Xiaodi Yan ◽

Hainan Zhao ◽

Yajie Yang ◽

...

Keyword(s):

Ionizing Radiation ◽

Lung Injury ◽

Mouse Model ◽

Tumor Cells ◽

Nuclear Translocation ◽

Lung Tumor ◽

Lung Epithelial Cells ◽

Normal Lung ◽

Limiting Factor ◽

Radiation Induced

AbstractThe lung is one of the most sensitive tissues to ionizing radiation, thus, radiation-induced lung injury (RILI) stays a key dose-limiting factor of thoracic radiotherapy. However, there is still little progress in the effective treatment of RILI. Ras-related C3 botulinum toxin substrate1, Rac1, is a small guanosine triphosphatases involved in oxidative stress and apoptosis. Thus, Rac1 may be an important molecule that mediates radiation damage, inhibition of which may produce a protective effect on RILI. By establishing a mouse model of radiation-induced lung injury and orthotopic lung tumor-bearing mouse model, we detected the role of Rac1 inhibition in the protection of RILI and suppression of lung tumor. The results showed that ionizing radiation induces the nuclear translocation of Rac1, the latter then promotes nuclear translocation of P53 and prolongs the residence time of p53 in the nucleus, thereby promoting the transcription of Trp53inp1 which mediates p53-dependent apoptosis. Inhibition of Rac1 significantly reduce the apoptosis of normal lung epithelial cells, thereby effectively alleviating RILI. On the other hand, inhibition of Rac1 could also significantly inhibit the growth of lung tumor, increase the radiation sensitivity of tumor cells. These differential effects of Rac1 inhibition were related to the mutation and overexpression of Rac1 in tumor cells.

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Ionizing radiation results in a mixture of cellular outcomes including mitotic catastrophe, senescence, methuosis, and iron-dependent cell death

Cell Death and Disease ◽

10.1038/s41419-020-03209-y ◽

2020 ◽

Vol 11 (11) ◽

Author(s):

Sandy Adjemian ◽

Teodora Oltean ◽

Sofie Martens ◽

Bartosz Wiernicki ◽

Vera Goossens ◽

...

Keyword(s):

Cell Death ◽

Ionizing Radiation ◽

Cell Lines ◽

Case Reports ◽

Cellular Responses ◽

Mitotic Catastrophe ◽

High Dose ◽

X Rays ◽

Cytotoxic Treatment ◽

Dependent Cell

AbstractRadiotherapy is commonly used as a cytotoxic treatment of a wide variety of tumors. Interestingly, few case reports underlined its potential to induce immune-mediated abscopal effects, resulting in regression of metastases, distant from the irradiated site. These observations are rare, and apparently depend on the dose used, suggesting that dose-related cellular responses may be involved in the distant immunogenic responses. Ionizing radiation (IR) has been reported to elicit immunogenic apoptosis, necroptosis, mitotic catastrophe, and senescence. In order to link a cellular outcome with a particular dose of irradiation, we performed a systematic study in a panel of cell lines on the cellular responses at different doses of X-rays. Remarkably, we observed that all cell lines tested responded in a similar fashion to IR with characteristics of mitotic catastrophe, senescence, lipid peroxidation, and caspase activity. Iron chelators (but not Ferrostatin-1 or vitamin E) could prevent the formation of lipid peroxides and cell death induced by IR, suggesting a crucial role of iron-dependent cell death during high-dose irradiation. We also show that in K-Ras-mutated cells, IR can induce morphological features reminiscent of methuosis, a cell death modality that has been recently described following H-Ras or K-Ras mutation overexpression.

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