Downregulation of BMI-1 enhances 5-fluorouracil-induced apoptosis in nasopharyngeal carcinoma cells

Qin, Li; Xing, Zhou; Zhang, Ling; Feng, Yan; Weng, Gui Xiang; Li, Man Zhi; Kong, Qing Li; Qian, Chao Nan; Zeng, Yi Xin; Zeng, Mu Sheng; Liao, Di; Song, Li

doi:10.1016/j.bbrc.2008.04.117

Cited by 59 publications

(54 citation statements)

References 25 publications

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“…Thus, our data are consistent with recent reports of apoptosis induction in tumor cells following BMI1 knockdown and 5-FU treatment. 17,18 Some of the proposed mechanisms include re-expression of p16 or signaling through PI3K. To that end, we examined P16 expression in C666-1 cells depleted of BMI1.…”

Section: Discussionmentioning

confidence: 99%

Targeted depletion of BMI1 sensitizes tumor cells to P53-mediated apoptosis in response to radiation therapy

et al. 2009

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Overexpression of BMI1 correlates with cancer development, progression, and therapy failure; however, the underlying molecular mechanisms remain to be fully elucidated. Using the C666-1 nasopharyngeal cancer (NPC) model, the role of BMI1 in mediating response of NPC cells to radiation therapy (RT) was investigated. The results showed a novel radioresistance function for BMI1 in NPC, wherein BMI1 depletion sensitized NPC cells to RT. Cell cycle analysis and transmission electron microscopy (TEM) showed apoptosis as the major mode of cell death, and the mitochondria as a primary targeted cellular organelle. Genomewide microarray and pathway analyses revealed that the P53 pathway is a critical mediator of this process. Cotransfection with siP53 rescued C666-1 cells from cytotoxicity upon BMI1 depletion and RT, thereby corroborating the role for P53. Pretreatment with the antioxidant, Trolox, inhibited apoptosis, indicating that production of reactive oxygen species (ROS) is also mediating cytotoxicity. In vivo, BMI1 depletion combined with RT abrogated tumor-forming capacity in SCID mice, showing the relevance of this process in a more complex tumor environment. Hence, we show a novel role for BMI1 in conferring radioresistance in cancer cells through the downregulation of p53-mediated apoptosis. These results suggest a potential strategy of BMI1 depletion combined with RT for tumors wherein BMI1 appears to be driving disease progression.

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Section: Discussionmentioning

confidence: 99%

Targeted depletion of BMI1 sensitizes tumor cells to P53-mediated apoptosis in response to radiation therapy

et al. 2009

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“…Some previous studies have shown that Bmi1 expression is a potential escape mechanism and associated with markedly increased likelihood of treatment failure and disease relapse after surgery [25,26] . Qin et al [27] have found that down-regulation of Bmi-1 enhances 5-fluorouracil-induced apoptosis in nasopharyngeal carcinoma cells and have suggested that the combination of 5-FU treatment and Bmi-1 depletion might be a potential clinical strategy for cancer chemotherapy. However, we believe that further investigations on larger series of ESCC patients, including clinical follow-up and novel molecular techniques, are needed to confirm our conclusions.…”

Section: B Amentioning

confidence: 99%

Association between Bmi1 and clinicopathological status of esophageal squamous cell carcinoma

Cao²,

Ji³

et al. 2009

WJG

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AIM:To investigate the clinicopathological roles of Bmi1 in esophageal squamous cell carcinoma (ESCC). METHODS:Quantitative real-time polymerase chain reaction and immunohistochemical staining for Bmi1 were performed in cancerous and adjacent noncancerous paraffin-embedded esophageal specimens. RESULTS:The Bmi1 expression level was unaffected by gender and age. The level of Bmi1 mRNA in ESCC was significantly higher than that in the adjacent noncancerous tissues (2.181 ± 2.158 vs 0.931 ± 0.894, P = 0.0152), and its over-expression was aggressively associated with lymph node metastasis (3.580 ± 2.487 vs 1.703 ± 0.758, P = 0.0003), poorer cell differentiation (P = 0.0000) and advanced pathological stage (3.827 ± 2.673 vs 1.590 ± 0.735, P = 0.0001). The patients were divided into high-expression and low-expression groups based on the median expression level of Bmi1 mRNA, and a shorter overall survival time in the former group was observed. Immunohistochemistry for Bmi1 oncoprotein showed diffusely positive, focally positive and negative expression in 44, 16 and 10 of 70 ESCC cases, respectively, compared with three, two and five of 10 adjacent non-cancerous cases (P = 0.027). The positive rate of the oncoprotein in samples of histological grade Ⅲ was higher than that of grade Ⅱ (P = 0.031), but its expression had no relation to the lymph node metastasis and pathological staging. In 70 ESCC samples, Bmi1 showed high intense expression in the cytoplasm and less or even no expression in the nucleus. CONCLUSION:Bmi1 was over-expressed in ESCC. Increased Bmi1 mRNA expression was significantly associated with ESCC progression, and the oncoprotein was largely distributed in the cytoplasm of tumor cells.

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“…Isolation and culture of VSMCs Primary VSMCs were derived from the thoracic aorta of adult male Sprague-Dawley (SD) rats as described previously [24,25] . Rat aortic VSMCs were isolated from the thoracic aortas of sixweek-old male SD rats using the explant technique [26] .…”

Section: Reagentsmentioning

confidence: 99%

“…Western blot analysis was performed as previously described [24,29,30] . Briefly, cells were lysed in a buffer containing 10 mmol/L HEPES (pH 7.9), 1.5 mmol/L MgCl 2 , 10 mmol/L KCl and 0.5% NP-40, and the cell lysates were centrifuged at 13 000 r/min for 15 min at 4 °C.…”

Section: Western Blot Analysesmentioning

confidence: 99%

Ezetimibe suppresses cholesterol accumulation in lipid-loaded vascular smooth muscle cells in vitro via MAPK signaling

Qin

Yang

et al. 2014

Acta Pharmacol Sin

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Aim: To investigate the mechanisms of anti-atherosclerotic action of ezetimibe in rat vascular smooth muscle cells (VSMCs) in vitro. Methods: VSMCs of SD rats were cultured in the presence of Chol:MβCD (10 μg/mL) for 72 h, and intracellular lipid droplets and cholesterol levels were evaluated using Oil Red O staining, HPLC and Enzymatic Fluorescence Assay, respectively. The expression of caveolin-1, sterol response element-binding protein-1 (SREBP-1) and ERK1/2 were analyzed using Western blot assays. Translocation of SREBP-1 and ERK1/2 was detected with immunofluorescence. Results: Treatment with Chol:MβCD dramatically increased the cellular levels of total cholesterol (TC), cholesterol ester (CE) and free cholesterol (FC) in VSMCs, which led to the formation of foam cells. Furthermore, Chol:MβCD treatment significantly decreased the expression of caveolin-1, and stimulated the expression and nuclear translocation of SREBP-1 in VSMCs. Co-treatment with ezetimibe (3 μmol/L) significantly decreased the cellular levels of TC, CE and FC, which was accompanied by elevation of caveolin-1 expression, and by a reduction of SREBP-1 expression and nuclear translocation. Co-treatment with ezetimibe dose-dependently decreased the expression of phosphor-ERK1/2 (p-ERK1/2) in VSMCs. The ERK1/2 inhibitor PD98059 (50 μmol/L) altered the cholesterol level and the expression of p-ERK1/2, SREBP-1 and caveolin-1 in the same manner as ezetimibe did. Conclusion: Ezetimibe suppresses cholesterol accumulation in rat VSMCs in vitro by regulating SREBP-1 and caveolin-1 expression, possibly via the MAPK signaling pathway.

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Downregulation of BMI-1 enhances 5-fluorouracil-induced apoptosis in nasopharyngeal carcinoma cells

Cited by 59 publications

References 25 publications

Targeted depletion of BMI1 sensitizes tumor cells to P53-mediated apoptosis in response to radiation therapy

Targeted depletion of BMI1 sensitizes tumor cells to P53-mediated apoptosis in response to radiation therapy

Association between Bmi1 and clinicopathological status of esophageal squamous cell carcinoma

Ezetimibe suppresses cholesterol accumulation in lipid-loaded vascular smooth muscle cells in vitro via MAPK signaling

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