scholarly journals AdipoR1 Regulates Ionizing Radiation-Induced Ferroptosis in HCC Cells Through Nrf2/xCT Pathway

2021 ◽  
Author(s):  
Hao Feng ◽  
Yi Liu ◽  
Yuhan Gan ◽  
Mengke Li ◽  
Rui Liu ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Cell Death ◽  
Ionizing Radiation ◽  
Radiation Sensitivity ◽  
Carcinoma Cells ◽  
Luciferase Reporter ◽  
Mrna And Protein Expression ◽  
Radiation Induced ◽  
Hepatic Cell Lines ◽  
Hcc Cells

Abstract Background: Ferroptosis is a type of cell death accompanied by iron-dependent lipid peroxidation, however, how IR-induced ferroptosis is regulated in Hepatocellular carcinoma cells (HCC) remains largely unknown. We have previously found that adiponectin receptor 1(AdipoR1) might be a prognostic biomarker for HCC after stereotactic body radiotherapy (SBRT). In this study, we aimed to elucidate the roles of AdipoR1 in radiation-induced Ferroptosis of HCC.Methods: Human HCC cell line MHCC-97H and HepG2 and human hepatic cell lines LO2 were tested. qRT-PCR and western blotting were used to detect mRNA and protein expression respectively, colony formation assay was used to evaluate the radiosensitivity and flow cytometry was used to assess lipid peroxidation and cell death. Dual-Luciferase Reporter assay system was used to detect the transcription activity. Results: Ionizing Radiation (IR) upregulated the expression of AdipoR1 in HCC cells and AdipoR1 knockdown could promote radiation sensitivity of HCC cells. AdipoR1 knockdown could decrease the expression of Nrf2 and Nrf2 protein stability. Nrf2 could bind to xCT promoter and promoted the transcription and expression of xCT. AdipoR1 knockdown increased significantly lipid peroxidation and ferroptosis induced by IR or Erastin respectively, which could be abolished by overexpression of Nrf2 and xCT.Conclusion: AdipoR1 knockdown can promote radiation sensitivity of HCC cells; AdipoR1 regulates IR-induced cell death by AdipoR1-Nrf2-xCT pathway.

scholarly journals Pharmacologic Profiling of Phosphoinositide 3-Kinase Inhibitors as Mitigators of Ionizing Radiation–Induced Cell Death

2013 ◽  
Vol 347 (3) ◽  
pp. 669-680 ◽  
Author(s):  
John S. Lazo ◽  
Elizabeth R. Sharlow ◽  
Michael W. Epperly ◽  
Ana Lira ◽  
Stephanie Leimgruber ◽  
...  
Keyword(s):  
Cell Death ◽  
Ionizing Radiation ◽  
Kinase Inhibitors ◽  
Radiation Induced ◽  
Phosphoinositide 3 Kinase

Chemical chaperones reduce ionizing radiation-induced endoplasmic reticulum stress and cell death in IEC-6 cells

2014 ◽  
Vol 450 (2) ◽  
pp. 1005-1009 ◽  
Author(s):  
Eun Sang Lee ◽  
Hae-June Lee ◽  
Yoon-Jin Lee ◽  
Jae-Hoon Jeong ◽  
Seongman Kang ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Ionizing Radiation ◽  
Endoplasmic Reticulum Stress ◽  
Chemical Chaperones ◽  
Radiation Induced

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

2021 ◽  
Vol 2021 ◽  
pp. 1-22
Author(s):  
Pengfei Yang ◽  
Xiangxia Luo ◽  
Jin Li ◽  
Tianyi Zhang ◽  
Xiaoling Gao ◽  
...  
Keyword(s):  
Cell Death ◽  
Ionizing Radiation ◽  
Tumor Cells ◽  
Metabolic Flux ◽  
Glutamine Metabolism ◽  
X Rays ◽  
Ros Accumulation ◽  
Intracellular Ros ◽  
Radiation Induced ◽  
Excessive Accumulation

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.

scholarly journals MiR-375 gene therapy attenuates drug resistance of hepatocellular carcinoma cells by inhibiting cell autophagy

2020 ◽  
Author(s):  
Dan Wang ◽  
Jingbo Yang
Keyword(s):  
Hepatocellular Carcinoma ◽  
Drug Resistance ◽  
Western Blotting ◽  
Regulatory Mechanism ◽  
Negative Control ◽  
Carcinoma Cells ◽  
Luciferase Reporter ◽  
Sorafenib Treatment ◽  
Hcc Cells ◽  
Dual Luciferase Reporter Assay

Abstract Objective To probe into the regulatory mechanism of miR-375 in hepatocellular carcinoma (HCC) cells under sorafenib treatment. Methods Western blotting and qRT-PCR were applied to measure the expressions of miR-375 and SIRT5 in parental HCC cells (HepG2 and Huh7) and sorafenib-resistant HCC cells (HepG2/so and Huh7/so). HepG2/so cells were accordingly transfected with miR-375 mimic, miR-375 inhibitor, sh-SIRT5, pcDNA3.1-SIRT5 or negative control. Western blotting measured the expressions of p62, LC3I and LC3II in HCC cells. CCK-8 and flow cytometry assessed the survivability and apoptosis of HCC cells, respectively. Bioinformatics techniques and dual-luciferase reporter assay predicted and verified the targeting relationship between miR-375 and SIRT5. Results MiR-375 was under-expressed and SIRT5 was over-expressed in HCC cells. Autophagy inhibitor impaired the survival of HepG2/so cells transfected with miR-375 inhibitor. Autophagy activator enhanced the drug resistance of HepG2/so cells transfected with miR-375 mimic. MiR-375 suppressed the drug resistance of HepG2/so cells by inhibiting autophagy. SIRT5 enhanced the drug resistance of HepG2/so cells by promoting autophagy and it could be targeted by miR-375. Conclusion MiR-375 suppresses autophagy to attenuate the drug resistance of HCC cells by regulating SIRT5. The findings of this study may provide new therapeutic targets for treating hepatocellular carcinoma.

scholarly journals Oncogenic Activation of YAP Signaling Sensitizes Ferroptosis of Hepatocellular Carcinoma via ALOXE3-Mediated Lipid Peroxidation Accumulation

2021 ◽  
Vol 9 ◽  
Author(s):  
Yifei Qin ◽  
Zhuo Pei ◽  
Zhuan Feng ◽  
Peng Lin ◽  
Shijie Wang ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Cell Death ◽  
Cancer Cell ◽  
Critical Role ◽  
Death Process ◽  
Hippo Signaling ◽  
Epithelial Tumor ◽  
Sorafenib Treatment ◽  
Potential Biomarker ◽  
Hcc Cells

Ferroptosis, a form of programmed cell death process driven by iron-dependent lipid peroxidation, plays an important role in tumor suppression. Although previous study showed that intracellular Merlin-Hippo signaling suppresses ferroptosis of epithelial tumor cells through the inactivation of YAP signaling, it remains elusive if the proto-oncogenic transcriptional co-activator YAP could serve as a potential biomarker to predict cancer cell response to ferroptosis-inducing therapies. In this study, we show that both total YAP staining and nuclear YAP staining were more prevalent in HCC tissues than in nontumorous regions. Compared to low-density HCC cells, high-density cells showed decreased nuclear localization of YAP and conferred significant resistance to ferroptosis. Oncogenic activation of YAP signaling by overexpression of YAP(S127A) mutant sensitized ferroptosis of HCC cells cultured in confluent density or in the 3D tumor spheroid model. Furthermore, we validated the lipoxygenase ALOXE3 as a YAP-TEAD target gene that contributed to YAP-promoted ferroptosis. Overexpression of ALOXE3 effectively increased the vulnerability of HCC cells to ferroptotic cell death. In an orthotopic mouse model of HCC, genetic activation of YAP rendered HCC cells more susceptible to ferroptosis. Finally, an overall survival assay further revealed that both a high expression of YAP and a low expression of GPX4 were correlated with increased survival of HCC patients with sorafenib treatment, which had been proven to be an inducer for ferroptosis by inhibition of the xc-amino acid antiporter. Together, this study unveils the critical role of intracellular YAP signaling in dictating ferroptotic cell death; it also suggests that pathogenic alterations of YAP signaling can serve as biomarkers to predict cancer cell responsiveness to future ferroptosis-inducing therapies.

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