Cytolethal Distending Toxin Enhances Radiosensitivity in Prostate Cancer Cells by Regulating Autophagy

Lin, Hwai Jeng; Liu, Hsin-Ho; Lin, Chia‐Der; Kao, Min-Chuan; Chen, Yuan; Chiang-Ni, Chuan; Jiang, Zhi-Pei; Huang, Mei-Zi; Lin, Ching-Yu; Lo, U‐Ging; Lin, Li-Chiung; Lai, Cheng-Chou; H, Lin; Hsieh, Jer‐Tsong; Chiu, Cheng-Hsun; Lai, Chih‐Ho

doi:10.3389/fcimb.2017.00223

Cited by 19 publications

(17 citation statements)

References 35 publications

(50 reference statements)

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“…PC3-KD cells were treated with simvastatin alone (100 μM), IR alone (2 Gy), or simvastatin combined with IR for 48 h. The treated cells were prepared and stained with 20 μg/ml propidium iodide (Sigma-Aldrich) for 1 h. The stained cells were determined by FACScalibur flow cytometer (Becton-Dickinson, San Jose, CA, United States) and the cell cycle distribution was assessed by using Cell Quest software WinMDI (Verity Software House, Topsham, ME, United States) as described previously ( Lin et al, 2017 ).…”

Section: Methodsmentioning

confidence: 99%

Simvastatin Sensitizes Radioresistant Prostate Cancer Cells by Compromising DNA Double-Strand Break Repair

et al. 2018

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Prostate cancer (PCa) is one of the most prevalent male cancers in western world. Radiation therapy (RT) is commonly used to treat PCa patients. However, a certain proportion of patients develop radioresistant PCa cells, which results in metastatic disease. Statins, which inhibit 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase, are commonly used to treat hypercholesterolemia, exhibiting beneficial effects on cardiovascular diseases and on several types of cancers, including PCa. However, the mechanistic details and crosstalk between statins and RT in PCa cells remain unknown. In this study, radioresistant DOC-2/DAB2 interactive protein (DAB2IP)-deficient PCa cells were used to evaluate whether simvastatin could enhance the effect of ionizing radiation (IR). The crucial molecules that associated with simvastatin elevated radiosensitivity in PCa cells were explored. Our results demonstrated that a combination treatment with simvastatin and IR synergistically induced apoptosis of radioresistant PCa cells. In addition, simvastatin appeared to compromise DNA double-strand breaks repair by activating the expressions of histone 2A family member X (γ-H2AX) and phospho-checkpoint kinase 1 (p-CHK1), suggesting an underlying mechanism for this radiosensitization of PCa cells. These findings reveal that simvastatin may be a potent therapeutic agent for co-treatment with radiation to overcome radioresistance in PCa cells.

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Section: Methodsmentioning

confidence: 99%

Simvastatin Sensitizes Radioresistant Prostate Cancer Cells by Compromising DNA Double-Strand Break Repair

et al. 2018

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“…According to previous studies, HMGB1 was revealed to be strongly associated with the occurrence and progression of tumors, and its expression level has been connected with the radiosensitivity of various types of cancers (8)(9)(10)(11), however, the underlying mechanism is unclear. In the present study, the expression level of HMGB1 was detected in both esophageal cancer tissues and cell lines.…”

Section: Introductionmentioning

confidence: 99%

Radiosensitization of esophageal carcinoma cells by knockdown of HMGB1 expression

et al. 2018

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Radiotherapy (RT) is a traditional and important treatment for carcinoma of the esophagus along with surgery and chemotherapy. High mobility group box 1 (HMGB1) plays a crucial part in inhibiting the apoptosis of cancer cells after irradiation treatment. The present study, was designed to analyze the function of HMGB1 in esophageal cancer progression and elucidate the effects of HMGB1 on the radiosensitivity of human esophageal cancer cell lines. In the present study, an immunohistochemical evaluation of HMGB1 was performed on 77 biopsies, and the results revealed that HMGB1 overexpression was positively correlated with gross tumor volume (GTV), tumor-node-metastasis (TNM) stage, T classification, distant metastasis, and relapse and negatively correlated with patient survival rates, suggesting that HMGB1 acts as a key factor in the development of esophageal cancer. An shRNA targeting HMGB1 was designed for the knockdown of HMGB1 in ECA109 and TE13 cells, and the transfection efficiency of the shRNA was assessed using quantitative real-time reverse transcription polymerase chain reaction and western blot analysis. CCK-8 and clonogenic assays were used to analyze the effect of HMGB1 on the proliferation and radiosensitivity, respectively, of esophageal cancer cells in vitro. The influence of HMGB1 on radiation-induced changes in the migration, invasion, and cell cycle as well as apoptosis of tumor cells was examined by wound-healing and Transwell assays and flow cytometry, respectively. In addition, xenograft tumor models were constructed to observe the effect of HMGB1 on tumor growth in vivo. The results of the study in vitro revealed that the proliferation of the HMGB1-shRNA group decreased after irradiation, and the radiation treatment reduced the tumor volume of the xenograft model which was more marked in HMGB1-shRNA group. Moreover, HMGB1 was involved in the phosphorylation of H2AX after irradiation, and HMGB1 knockdown blocked the cell cycle in the G0/G1 phase and increased apoptosis. HMGB1 deficiency was also correlated with the upregulation of p16, Bax and caspase-9 and the downregulation of MMP-2, MMP-9, cyclin D1, CDK4, γH2AX and Bcl-2. These data indicated that the overexpression of HMGB1 prior to treatment was correlated with poor clinical outcome in esophageal carcinoma and that knockdown HMGB1 expression in human esophageal cancer cell lines increased their radiosensitivity by allowing the induction of apoptosis and G0/G1 arrest after exposure to radiation.

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“…Numerous reports have demonstrated that mTOR kinase suppresses autophagy and apoptosis ( Wang et al, 2015 ) via interference with Atg protein-related formation of autophagosomes ( Levine and Yuan, 2005 ). The PI3K/Akt/mTOR signaling pathways are key axes involved in anticancer drug-induced autophagy, including PCa treatment ( Kim et al, 2017 ; Lin et al, 2017 ; Yu et al, 2017 ). This largely explains the effectiveness of mTOR inhibitors, such as rapamycin, as anticancer agents.…”

Section: Discussionmentioning

confidence: 99%

“…Experimental and clinical data indicate that the mTOR pathway, and its upstream regulators in the PI3K/PTEN/Akt cascade, are altered in a wide variety of human malignancies ( Ciuffreda et al, 2010 ). PI3K/Akt/mTOR complex-1 (mTORC1) and the androgen receptor are two major drivers of PCa, and the PI3K/Akt/mTOR signaling pathway plays a key role in anticancer drug-mediated regulation of autophagy in human PCa cells ( Wang et al, 2016 ; Kim et al, 2017 ; Lin et al, 2017 ). Previous studies have also revealed that the degree of activation of Akt/mTOR signaling components is important, as too little or too much signaling has different consequences depending on the PCa state ( Farrow et al, 2014 ).…”

Section: Introductionmentioning

confidence: 99%

Qianlie Xiaozheng Decoction Induces Autophagy in Human Prostate Cancer Cells via Inhibition of the Akt/mTOR Pathway

Xu¹,

Cai

Zong³

et al. 2018

Front. Pharmacol.

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Qianlie Xiaozheng decoction (QLXZD), a traditional Chinese medicinal formula, has been used clinically to treat advanced prostate cancer (PCa) for more than 10 years. However, experimental evidence supporting its efficacy is lacking. Here, we investigated the anticancer properties and molecular mechanism of QLXZD in vitro in a human PCa cell line (PC3) and in vivo using PC3 xenografts in nude mice. We confirmed the antineoplastic activity of QLXZD by analyzing cell viability and tumor volume growth, which decreased significantly compared to that of the controls. Autophagy following QLXZD treatment was detected morphologically using transmission electron microscopy and was confirmed by measuring the expression of autophagy markers (LC3-II and p62) using fluorescence analysis, flow cytometry, and western blotting. Increasing autophagic flux induced by QLXZD was monitored via pmCherry-GFP-LC3 fluorescence analysis. QLXZD-induced autophagic cell death was alleviated by the autophagy inhibitors, 3-methyl adenine and hydroxychloroquine. We evaluated the total expression and phosphorylation levels of proteins involved in the Akt/mTOR pathway regulating autophagy. Phosphorylation of Akt, mTOR, and p70S6K, but not total protein levels, decreased following treatment. This is the first study to demonstrate the autophagy-related mechanistic pathways utilized during QLXZD-mediated antitumor activity both in vitro and in vivo. These findings support the clinical use of QLXZD for PCa treatment.

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Cytolethal Distending Toxin Enhances Radiosensitivity in Prostate Cancer Cells by Regulating Autophagy

Cited by 19 publications

References 35 publications

Simvastatin Sensitizes Radioresistant Prostate Cancer Cells by Compromising DNA Double-Strand Break Repair

Simvastatin Sensitizes Radioresistant Prostate Cancer Cells by Compromising DNA Double-Strand Break Repair

Radiosensitization of esophageal carcinoma cells by knockdown of HMGB1 expression

Qianlie Xiaozheng Decoction Induces Autophagy in Human Prostate Cancer Cells via Inhibition of the Akt/mTOR Pathway

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