scholarly journals PSP1, a Phosphatidylserine-Recognizing Peptide, Is Useful for Visualizing Radiation-Induced Apoptosis in Colorectal Cancer In Vitro and In Vivo

2018 ◽  
Vol 11 (4) ◽  
pp. 1044-1052 ◽  
Author(s):  
Sang Mun Bae ◽  
Soo Jung Park ◽  
Myoungeun Choi ◽  
Miyeoun Song ◽  
Young Eun Cho ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Radiation Induced ◽  
Induced Apoptosis

scholarly journals Necroptosis regulates tumor repopulation after radiotherapy via RIP1/RIP3/MLKL/JNK/IL8 pathway

2019 ◽  
Vol 38 (1) ◽  
Author(s):  
Yiwei Wang ◽  
Minghui Zhao ◽  
Sijia He ◽  
Yuntao Luo ◽  
Yucui Zhao ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Growth Stimulation ◽  
Underlying Mechanism ◽  
Promoting Effect ◽  
Clinical Prognosis ◽  
Associated Proteins ◽  
Radiation Induced ◽  
Colorectal Cancer Patients

Abstract Background Tumor cell repopulation after radiotherapy is a major cause for the tumor radioresistance and recurrence. This study aims to investigate the underlying mechanism of tumor repopulation after radiotherapy, with focus on whether and how necroptosis takes part in this process. Methods Necroptosis after irradiation were examined in vitro and in vivo. And the growth-promoting effect of necroptotic cells was investigated by chemical inhibitors or shRNA against necroptosis associated proteins and genes in in vitro and in vivo tumor repopulation models. Downstream relevance factors of necroptosis were identified by western blot and chemiluminescent immunoassays. Finally, the immunohistochemistry staining of identified necroptosis association growth stimulation factor was conducted in human colorectal tumor specimens to verify the relationship with clinical outcome. Results Radiation-induced necroptosis depended on activation of RIP1/RIP3/MLKL pathway, and the evidence in vitro and in vivo demonstrated that the inhibition of necroptosis attenuated growth-stimulating effects of irradiated tumor cells on living tumor reporter cells. The JNK/IL-8 were identified as downstream molecules of pMLKL during necroptosis, and inhibition of JNK, IL-8 or IL-8 receptor significantly reduced tumor repopulation after radiotherapy. Moreover, the high expression of IL-8 was associated with poor clinical prognosis in colorectal cancer patients. Conclusions Necroptosis associated tumor repopulation after radiotherapy depended on activation of RIP1/RIP3/MLKL/JNK/IL-8 pathway. This novel pathway provided new insight into understanding the mechanism of tumor radioresistance and repopulation, and MLKL/JNK/IL-8 could be developed as promising targets for blocking tumor repopulation to enhance the efficacy of colorectal cancer radiotherapy.

Transfection of PDCD5 sensitizes colorectal cancer cells to cisplatin-induced apoptosis in vitro and in vivo

2010 ◽  
Vol 649 (1-3) ◽  
pp. 120-126 ◽  
Author(s):  
Anning Yin ◽  
Yingan Jiang ◽  
Xianfeng Zhang ◽  
Juan Zhao ◽  
Hesheng Luo
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cells ◽  
Colorectal Cancer Cells ◽  
Induced Apoptosis

scholarly journals Synergistic antitumor effect of 5-fluorouracil with the novel LSD1 inhibitor ZY0511 in colorectal cancer

2020 ◽  
Vol 12 ◽  
pp. 175883592093742
Author(s):  
Wen Peng ◽  
Huaqing Zhang ◽  
Shisheng Tan ◽  
Yan Li ◽  
Yang Zhou ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Antitumor Effect ◽  
Underlying Mechanism ◽  
Synergistic Antitumor Effect ◽  
Anticancer Effects ◽  
Potential Marker ◽  
And Migration ◽  
Induced Apoptosis

Background: Lysine-specific histone demethylase 1 (LSD1) is a potential target of cancer therapy. In the present study, we aimed to investigate the combined antitumor activity of a novel LSD1 inhibitor (ZY0511) with 5-fluorouracil (5-FU) and elucidate the underlying mechanism in colorectal cancer (CRC). Methods: We evaluated LSD1 expression in CRC tissues from patients who received 5-FU treatment. The synergistic antitumor effect of 5-FU with ZY0511 against human CRC cells was detected both in vitro and in vivo. The underlying mechanism was explored based on mRNA sequencing (mRNA-seq) technology. Results: Overexpression of LSD1 was observed in human CRC tissues, and correlated with CRC development and 5-FU resistance. ZY0511, a novel LSD1 inhibitor, effectively inhibited CRC cells proliferation, both in vitro and in vivo. Notably, the combination of ZY0511 and 5-FU synergistically reduced CRC cells viability and migration in vitro. It also suppressed Wnt/β-catenin signaling and DNA synthesis pathways, which finally induced apoptosis of CRC cells. In addition, the combination of ZY0511 with 5-FU significantly reduced CRC xenograft tumor growth, along with lung and liver metastases in vivo. Conclusions: Our findings identify LSD1 as a potential marker for 5-FU resistance in CRC. ZY0511 is a promising candidate for CRC therapy as it potentiates 5-FU anticancer effects, thereby providing a new combinatorial strategy for treating CRC.

scholarly journals DR5 Knockout Mice Are Compromised in Radiation-Induced Apoptosis

2005 ◽  
Vol 25 (5) ◽  
pp. 2000-2013 ◽  
Author(s):  
Niklas Finnberg ◽  
Joshua J. Gruber ◽  
Peiwen Fei ◽  
Dorothea Rudolph ◽  
Anka Bric ◽  
...  
Keyword(s):  
Cell Death ◽  
Null Mouse ◽  
Organ Specific ◽  
Radiation Induced ◽  
Induced Apoptosis ◽  
The Brain ◽  
Necrosis Factor

ABSTRACT DR5 (also called TRAIL receptor 2 and KILLER) is an apoptosis-inducing membrane receptor for tumor necrosis factor-related apoptosis-inducing ligand (also called TRAIL and Apo2 ligand). DR5 is a transcriptional target of p53, and its overexpression induces cell death in vitro. However, the in vivo biology of DR5 has remained largely unexplored. To better understand the role of DR5 in development and in adult tissues, we have created a knockout mouse lacking DR5. This mouse is viable and develops normally with the exception of having an enlarged thymus. We show that DR5 is not expressed in developing embryos but is present in the decidua and chorion early in development. DR5-null mouse embryo fibroblasts expressing E1A are resistant to treatment with TRAIL, suggesting that DR5 may be the primary proapoptotic receptor for TRAIL in the mouse. When exposed to ionizing radiation, DR5-null tissues exhibit reduced amounts of apoptosis compared to wild-type thymus, spleen, Peyer's patches, and the white matter of the brain. In the ileum, colon, and stomach, DR5 deficiency was associated with a subtle phenotype of radiation-induced cell death. These results indicate that DR5 has a limited role during embryogenesis and early stages of development but plays an organ-specific role in the response to DNA-damaging stimuli.

scholarly journals IL-24-armed oncolytic vaccinia virus exerts potent antitumor effects via multiple pathways in colorectal cancer

2020 ◽  
Author(s):  
Lili Deng ◽  
Xue Yang ◽  
Jun Fan ◽  
Yuedi Ding ◽  
Ying Peng ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Vaccinia Virus ◽  
Cancer Cells ◽  
Treatment Options ◽  
Antitumor Effects ◽  
Colorectal Cancer Cells ◽  
Cancer Tumor ◽  
Induced Apoptosis

Colorectal cancer is an aggressive malignancy for which there are limited treatment options. Oncolytic vaccinia virus isbeing developed as a novel strategy for cancer therapy. Arming vaccinia virus with immunostimulatory cytokines can enhance the tumor cell-specific replication and antitumor efficacy. Interleukin-24 (IL-24) is an important immune mediator, as well as a broad-spectrum tumor suppressor. Here, we constructed a targeted vaccinia virus of Guang9 strain harbored IL-24 (VG9-IL-24) to evaluate its antitumor effects. In vitro, VG9-IL-24 induced increased number of apoptotic cells and blocked colorectal cancer cells in the G2/M phase of the cell cycle. VG9-IL-24 induced apoptosis in colorectal cancer cells via multiple apoptotic signaling pathways. In vivo,VG9-IL-24 significantly inhibited the tumor growth and prolonged the survival both in human and murine colorectal cancer models. Besides, VG9-IL-24 stimulated multiple antitumor immune responses and direct bystander antitumor activity. Our results indicate that VG9-IL-24 can inhibit the growth of colorectal cancer tumor by inducing oncolysis and apoptosis as well as stimulating the anti-tumor immune effects. These findings indicate that VG9-IL-24 may exert a potential therapeutic strategy for combating colorectal cancer

scholarly journals GW4064 Enhances the Chemosensitivity of Colorectal Cancer to Oxaliplatin by Inducing Pyroptosis

2020 ◽  
Author(s):  
Jing Guo ◽  
Jianbao Zheng ◽  
Zhengshui Xu ◽  
Chenye Zhao ◽  
Kui Yang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Farnesoid X Receptor ◽  
Antitumor Effects ◽  
In Vivo Experiments ◽  
Stat3 Signaling ◽  
Synergistic Mechanism ◽  
Combination Study ◽  
Induced Apoptosis

Abstract Background Repeated and long-term oxaliplatin therapy leads to drug resistance and severe adverse events, which limit its clinical use. These difficulties highlight the importance of identifying potent and specific drug combinations to enhance the antitumor effects of oxaliplatin. The farnesoid X receptor (FXR) deficiency in colorectal cancer (CRC) suggests that restoring FXR function might be a promising strategy for CRC treatment.Methods A series of in vitro and in vivo experiments were conducted to assess the antitumor effect of the combination of oxaliplatin and FXR agonist GW4064 in CRC. The synergistic mechanism involved was explored.Results A drug combination study showed that the GW4064 acted synergistically with oxaliplatin in colon cancer cells. The combination of oxaliplatin plus GW4064 inhibited cell growth and colony formation, induced apoptosis and pyroptosis in vitro, and slowed tumor growth in vivo. Mechanistically, GW4064 enhanced the chemosensitivity of cells to oxaliplatin by inducing BAX/caspase-3/GSDME-mediated pyroptosis. Furthermore, the combination of oxaliplatin and GW4064 synergistically inhibited STAT3 signaling by restoring SHP expression.Conclusions Our study revealed that GW4064 could enhance the antitumor effects of oxaliplatin against CRC, which provides a novel therapeutic strategy based on a combinational approach for CRC treatment.

scholarly journals Substituted Piperazines as Novel Potential Radioprotective Agents

Molecules ◽  
2020 ◽  
Vol 25 (3) ◽  
pp. 532
Author(s):  
Alzbeta Filipova ◽  
Jan Marek ◽  
Radim Havelek ◽  
Jaroslav Pejchal ◽  
Marcela Jelicova ◽  
...  
Keyword(s):  
Whole Body ◽  
Piperazine Derivatives ◽  
Radiation Induced ◽  
Low Toxicity ◽  
Increasing Risk ◽  
Low Cytotoxicity ◽  
Induced Apoptosis ◽  
Previous Series

The increasing risk of radiation exposure underlines the need for novel radioprotective agents. Hence, a series of novel 1-(2-hydroxyethyl)piperazine derivatives were designed and synthesized. Some of the compounds protected human cells against radiation-induced apoptosis and exhibited low cytotoxicity. Compared to the previous series of piperazine derivatives, compound 8 exhibited a radioprotective effect on cell survival in vitro and low toxicity in vivo. It also enhanced the survival of mice 30 days after whole-body irradiation (although this increase was not statistically significant). Taken together, our in vitro and in vivo data indicate that some of our compounds are valuable for further research as potential radioprotectors.

scholarly journals A KLF4/PiHL/EZH2/HMGA2 regulatory axis and its function in promoting oxaliplatin-resistance of colorectal cancer

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Xuan Deng ◽  
Fanyang Kong ◽  
Si Li ◽  
Haoqin Jiang ◽  
Liu Dong ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
In Vivo Models ◽  
Akt Phosphorylation ◽  
New Class ◽  
H3k27me3 Level ◽  
Tumor Tissues ◽  
Signaling Axis ◽  
Induced Apoptosis

AbstractLong noncoding RNAs (lncRNAs) have emerged as a new class of regulatory molecules implicated in therapeutic resistance, yet the mechanisms underlying lncRNA-mediated oxaliplatin resistance in colorectal cancer (CRC) are poorly understood. In this study, lncRNA P53 inHibiting LncRNA (PiHL) was shown to be highly induced in oxaliplatin-resistant CRC cells and tumor tissues. In vitro and in vivo models clarified PiHL’s role in conferring resistance to oxaliplatin-induced apoptosis. PiHL antagonized chemosensitivity through binding with EZH2, repressing location of EZH2 to HMGA2 promoter, and downregulating methylation of histone H3 lysine 27 (H3K27me3) level in HMGA2 promoter, thus activating HMGA2 expression. Furthermore, HMGA2 upregulation induced by PiHL promotes PI3K/Akt phosphorylation, which resulted in increased oxaliplatin resistance. We also found that transcription factor KLF4 was downregulated in oxaliplatin-resistant cells, and KLF4 negatively regulated PiHL expression by binding to PiHL promoter. In vivo models further demonstrated that treatment of oxaliplatin-resistant CRC with locked nucleic acids targeting PiHL restored oxaliplatin response. Collectively, this study established lncRNA PiHL as a chemoresistance promoter in CRC, and targeting PiHL/EZH2/HMGA2/PI3K/Akt signaling axis represents a novel choice in the investigation of drug resistance.

scholarly journals TRIM21–SERPINB5 aids GMPS repression to protect nasopharyngeal carcinoma cells from radiation-induced apoptosis

2019 ◽  
Author(s):  
Panpan Zhang ◽  
Xiaomin Li ◽  
Qiuping He ◽  
Lulu Zhang ◽  
Keqing Song ◽  
...  
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Carcinoma Cells ◽  
Head And Neck Malignancy ◽  
Neck Malignancy ◽  
Tripartite Motif ◽  
Radiation Induced ◽  
Induced Apoptosis ◽  
Epistatic Analysis

AbstractNasopharyngeal carcinoma (NPC) is the most prevalent head and neck malignancy in South China and Southeast Asia. The main NPC treatment strategy is radiotherapy. However, recurrence resulting from radioresistance is a leading clinical bottleneck. Revealing the mechanism of NPC radioresistance would help improve the therapeutic effect. Here, our work reveals thatTRIM21(tripartite motif–containing 21) functions as an oncogene in NPC progression, and its ablation increases NPC cell radiosensitivity. Further analysis indicated that TRIM21 represses TP53 expression by mediating GMPS (guanine monophosphate synthase) ubiquitination and degradation after ionizing radiation. Mass spectrometry and co-immunoprecipitation showed that SERPINB5 (serpin family B member 5) interacts with both TRIM21 and GMPS. Epistatic analysis showed that SERPINB5 acts as an adaptor to recruit GMPS and introduce TRIM21 for ubiquitination. The in vitro and in vivo results validated the finding that SERPINB5 promotes NPC cell radioresistance. Furthermore, immunohistochemistry indicated that radioresistant patients have higher SERPINB5 expression. Overall, our data show that TRIM21–SERPINB5-mediated GMPS degradation facilitates TP53 repression, which promotes the radioresistance of NPC cells.

scholarly journals Gambogenic Acid Induces Endoplasmic Reticulum Stress in Colorectal Cancer via the Aurora A Pathway

2021 ◽  
Vol 9 ◽  
Author(s):  
Cheng Liu ◽  
Jiaxin Xu ◽  
Chenxu Guo ◽  
Xugang Chen ◽  
Chunmei Qian ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Aurora A ◽  
Eukaryotic Translation ◽  
Induced Apoptosis

Colorectal cancer (CRC) is one of the most common malignancies in the world and has a poor prognosis. In the present research, gambogenic acid (GNA), isolated from the traditional Chinese medicine gamboge, markedly induced apoptosis and inhibited the proliferation of CRC in vitro and in vivo. Furthermore, GNA triggered endoplasmic reticulum (ER) stress, which subsequently activated inositol-requiring enzyme (IRE) 1α and the eukaryotic translation initiation factor (eIF) 2α pathway. Pretreatment with salubrinal (an eIF2α inhibitor) rescued GNA-induced cell death. Furthermore, GNA downregulated the expression of Aurora A. The Aurora A inhibitor alisertib decreased ER stress. In human colorectal adenocarcinoma tissue, Aurora A was upregulated compared to normal colorectal epithelial nuclei. Furthermore, GNA ameliorated mouse colitis-associated cancer models. Our findings demonstrated that GNA significantly inhibited the proliferation of CRC through activation of ER stress by regulating Aurora A, which indicates the potential of GNA for preventing the progression of CRC.

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