核桃醌诱导白血病HL-60细胞凋亡的作用及分子机制研究
摘要
核桃楸是我国的传统中药材,具有广泛的药理作用。近年来,国内外的许多研究表明,核桃楸在体内、外对多种肿瘤细胞有抑制作用。我们研究表明,核桃楸中抗肿瘤成分主要为核桃醌,其对人白血病HL-60细胞有明显的抑制作用,但详细的作用机制尚不明确。
本研究应用MTT法、荧光染色法、流式细胞术、实时荧光PCR和蛋白免疫印迹技术等方法,从形态学、基因及蛋白表达水平,探讨核桃醌诱导HL-60细胞凋亡的作用及分子机制。
研究结果表明:核桃醌通过上调Bax/Bcl-2的比率,增加线粒体膜通透性、降低线粒体膜电位,促进Cyt c、AIF和Smac等凋亡相关因子由线粒体向细胞质转移,导致caspase蛋白酶原的剪切活化,通过线粒体途径诱导HL-60细胞凋亡。此外,在核桃醌诱导细胞凋亡的同时,可检测到细胞内ROS产生增加和GSH含量减少;应用抗氧化剂NAC可降低Bax/Bcl-2的比率,改变线粒体膜电位,减弱Cyt c等凋亡相关因子向细胞质转移,抑制caspase蛋白酶原的激活,阻断核桃醌诱导细胞凋亡作用,提示核桃醌诱导HL-60细胞凋亡的作用与ROS的产生增加密切相关。核桃醌诱导HL-60细胞凋亡过程亦可能有ERK通路和PI3K/AKT通路的参与。
结论:核桃醌能刺激细胞内部ROS产生增加,消耗GSH,改变线粒体膜电位,通过线粒体途径诱导HL-60细胞凋亡。
Background:
Juglans Mandshurica Maxim, one of traditional Chinese herb, was known to induce apoptosis in a variety of tumor cells in vitro. Juglone, one of the main active components from the roots and barks of Juglans Mandshurica Maxim. However, the molecular mechanism of apoptosis induced by Juglone in HL-60 cell remains elusive. Nowadays, it is of particular significance to use molecular biological methods to study the pharmacologic effects of traditional Chinese herbs to reiterate the underlying pharmacological mechanism and to do research in finding new anti-tumor drugs, which has also become the trend in exploiting the Chinese medicine. In such a circumference, a deeper study on the molecular mechanism of Juglone in anti-tumor effect is promising and valuable.
Objects:
To investigate the molecular mechanism of apoptosis induced by Juglone in HL-60 cells.
Methods:
1. Fluorescence microscope was used to detect the morphological changes of nuclear chromatin stained by Hoechst 33342 and AO/EB.
2. Flow cytometric analysis was used to detect the percentage of apoptotic cells, mitochondrial membrane potential and ROS
3. Spectrophotometric method was used to detect the activities of caspase-3, -9 and the content of GSH.
4. Western blotting was used to detect the protein level of caspase-3, -9, Bcl-2, Bax, PARP, Smac, Cyt C and AIF.
5. QPCR to detect the gene changes of Bcl-2 and Bax.
6. Western blotting was used to detect the effect of NAC on the apoptotic protein expression.
7. Western blotting was used to detect the effect of Juglone on MAPK and PI3K/AKT pathway.
Results:
The main results were divided into some sections as follows:
1 Juglone inhibited HL-60 cells proliferation and induced apoptosis
1.1 Juglone inhibited HL-60 cells proliferation
The proliferation inhibition effect of Juglone on HL-60 cells was determined with the MTT colorimetric assay. MTT results showed that after treated with different dose Juglone for 24h, the proliferation inhibition rates of HL-60 cells were 13.56±2.87% 28.58±3.08%, 56.00±1.73%, 73.72±3.50% and 92.37±1.41%, respectively at various concentrations (0.39, 0.78, 1.56, 3.125, 6.25μg/ml) and at the dosage of 1.56μg/ml, the inhibition rate sharply rised to 56%. The IC50 was 1.5μg/ml. The results showed exposure of HL-60 cells to Juglone caused significant growth inhibition in a dose- and time-dependent manner.
1.2 Juglone induce apoptosis in HL-60 cell
1.2.1 Morphological changes
1.2.1.1 Hoechst 33342 fluorescent staining assay was used to observe cell apoptosis. The results showed the cells of control group appeared normal appearance. Cells Juglone-treated group showed typical apoptotical morphological changes, for example condensed or fragmented nuclei.
1.2.1.2 AO/EB double fluorescent staining assay was used to observe cell apoptosis. The results showed the apoptotic cells appeared in the cell Juglone-treated groups. Normal cells had a regular nuclear with green fluorimetric stain, while apoptotic cell had unregular nuclear with yellowish green stain and the capacity of cell became smaller.
1.2.2 Detect apoptosis by flow cytometry
1.2.2.1 PI staining assay was used to detect apoptosis. The results showed that the percentage of apoptotic cells was increased significantly from 0.16±0.04% to 28.42±4.76%.
1.2.2.2 Annexin V-FITC/PI double staining was used to detect cell apoptosis. The results showed that the percentage of apoptotic cells was increased significantly from 9.44±3.48% to 71.96±5.26%.
2 Molecular mechanism of apoptosis induced by Juglone in HL-60 cell
2.1 The effect of Juglone on the mitochondrial function
2.1.1 The effect of Juglone on the mitochondrial transmembrane potential (ΔΨm) The results showed thatΔΨm was decreased.
2.1.2 The effect of Juglone on the apoptotosis-related proteins expression
2.1.2.1 The effect of Juglone on the Bcl-2 and Bax
The results showed that Bax protein and gene expression was increased and Bcl-2 protein and gene expression was decreased. The ratio of Bax/Bcl-2 was increased. Results indicated that apoptosis induced by Juglone involved the changes of Bcl-2 family.
2.1.2.2 The effect of Juglone on the Cyt C, Smac and AIF proteins
The results showed that Juglone could increase the release Cyt C, Smac and AIF proteins from mitochondrion to cytoplasm in a dose- and time-dependent manner.
2.1.2.3 The effect of Juglone on the caspase-3, -9, PARP proteins expression and activity of caspase.
The results showed that procaspase-3 and procaspase-9 were cut and PARP substrate of caspase was decomposed along with the elevating of concentration. The activities of caspase-3, -9 were also increased in a dose- and time-dependent manner.
2.2 The effect of ROS on the apoptosis induced by Juglone in HL-60 cell
2.2.1 The effect of Juglone on ROS
The results showed that the ROS increased significantly with concentration 1.0 and 1.5μg/mL compared with control group. It indicated that the ROS could be increased by Juglone in HL-60 cells.
2.2.2 The effect of Juglone on GSH
Results showed that the content of GSH was significantly decreased. It indicated that Juglone could induce oxidative stress in HL-60 cells.
2.2.3 The effect of NAC on the apoptosis induced by Juglone in HL-60 cell
The results showed that the percentage of apoptotic cells was 6.85±1.89%, 7.71±2.54%, 82.26±10.85% and11.67±3.26%, respectively. It indicated that NAC could inhibit the apoptosis induced by Juglone.
2.2.4 The effect of NAC on the apoptotosis-related proteins expression
2.2.4.1 The effect of NAC on the Bcl-2 and Bax proteins expression
The results showed that NAC had no obviously effect on Bcl-2 and Bax proteins expression. Julgone could increase Bax protein expression and decrease Bcl-2 protein expression. The ratio of Bax/Bcl-2 was increased, While NAC could inhibit the procession.
2.2.4.2 The effect of NAC on the Cyt C and Smac proteins
The results showed that NAC had no obviously on Cyt C and Smac proteins. Juglone could increase the Cyt C and Smac protein releasing to cytoplasm, While NAC could inhibit the procession.
2.2.4.3 The effect of NAC on the caspase-3, -9 proteins expression
The results showed that NAC had no obviously effect on the procaspase-3 and procaspase-9 protein expression. Juglone could promote the procaspase-3 and procaspase-9 to cutting, while the NAC could inhibit the procession.
2.3 The effect of Juglone on the MAPK pathway
The results showed that Juglone had no obviously effect on the p38 and JNK protein levels. But Juglone promoted an increase of p-ERK in a dose dependent way. It suggested that the ERK involved in the apoptosis induced by Juglone.
2.4 The effect of Juglone on the PI3K/AKT pathway
The results showed that Juglone could induce a significant decrease p-AKT at 0.5μg/mL, p-AKT expression was inhibited by Juglone. It suggested that PI3K/AKT pathway involved in the apoptosis induced by Juglone.
Conclusion:
1. Juglone could inhibit the cell proliferation in a dose- and time-dependent manner.
2. Juglone could induce apoptosis in HL-60 cell.
3. Juglone could induce apoptosis through mitochondrial pathway in HL-60 cell.
4. Juglone could increase the ROS in HL-60 cells and activate the mitochondrial pathway to induce apoptosis.
5. Juglone could activate ERK pathway and inhibit PI3K/AKT pathway.
本研究应用MTT法、荧光染色法、流式细胞术、实时荧光PCR和蛋白免疫印迹技术等方法,从形态学、基因及蛋白表达水平,探讨核桃醌诱导HL-60细胞凋亡的作用及分子机制。
研究结果表明:核桃醌通过上调Bax/Bcl-2的比率,增加线粒体膜通透性、降低线粒体膜电位,促进Cyt c、AIF和Smac等凋亡相关因子由线粒体向细胞质转移,导致caspase蛋白酶原的剪切活化,通过线粒体途径诱导HL-60细胞凋亡。此外,在核桃醌诱导细胞凋亡的同时,可检测到细胞内ROS产生增加和GSH含量减少;应用抗氧化剂NAC可降低Bax/Bcl-2的比率,改变线粒体膜电位,减弱Cyt c等凋亡相关因子向细胞质转移,抑制caspase蛋白酶原的激活,阻断核桃醌诱导细胞凋亡作用,提示核桃醌诱导HL-60细胞凋亡的作用与ROS的产生增加密切相关。核桃醌诱导HL-60细胞凋亡过程亦可能有ERK通路和PI3K/AKT通路的参与。
结论:核桃醌能刺激细胞内部ROS产生增加,消耗GSH,改变线粒体膜电位,通过线粒体途径诱导HL-60细胞凋亡。
Background:
Juglans Mandshurica Maxim, one of traditional Chinese herb, was known to induce apoptosis in a variety of tumor cells in vitro. Juglone, one of the main active components from the roots and barks of Juglans Mandshurica Maxim. However, the molecular mechanism of apoptosis induced by Juglone in HL-60 cell remains elusive. Nowadays, it is of particular significance to use molecular biological methods to study the pharmacologic effects of traditional Chinese herbs to reiterate the underlying pharmacological mechanism and to do research in finding new anti-tumor drugs, which has also become the trend in exploiting the Chinese medicine. In such a circumference, a deeper study on the molecular mechanism of Juglone in anti-tumor effect is promising and valuable.
Objects:
To investigate the molecular mechanism of apoptosis induced by Juglone in HL-60 cells.
Methods:
1. Fluorescence microscope was used to detect the morphological changes of nuclear chromatin stained by Hoechst 33342 and AO/EB.
2. Flow cytometric analysis was used to detect the percentage of apoptotic cells, mitochondrial membrane potential and ROS
3. Spectrophotometric method was used to detect the activities of caspase-3, -9 and the content of GSH.
4. Western blotting was used to detect the protein level of caspase-3, -9, Bcl-2, Bax, PARP, Smac, Cyt C and AIF.
5. QPCR to detect the gene changes of Bcl-2 and Bax.
6. Western blotting was used to detect the effect of NAC on the apoptotic protein expression.
7. Western blotting was used to detect the effect of Juglone on MAPK and PI3K/AKT pathway.
Results:
The main results were divided into some sections as follows:
1 Juglone inhibited HL-60 cells proliferation and induced apoptosis
1.1 Juglone inhibited HL-60 cells proliferation
The proliferation inhibition effect of Juglone on HL-60 cells was determined with the MTT colorimetric assay. MTT results showed that after treated with different dose Juglone for 24h, the proliferation inhibition rates of HL-60 cells were 13.56±2.87% 28.58±3.08%, 56.00±1.73%, 73.72±3.50% and 92.37±1.41%, respectively at various concentrations (0.39, 0.78, 1.56, 3.125, 6.25μg/ml) and at the dosage of 1.56μg/ml, the inhibition rate sharply rised to 56%. The IC50 was 1.5μg/ml. The results showed exposure of HL-60 cells to Juglone caused significant growth inhibition in a dose- and time-dependent manner.
1.2 Juglone induce apoptosis in HL-60 cell
1.2.1 Morphological changes
1.2.1.1 Hoechst 33342 fluorescent staining assay was used to observe cell apoptosis. The results showed the cells of control group appeared normal appearance. Cells Juglone-treated group showed typical apoptotical morphological changes, for example condensed or fragmented nuclei.
1.2.1.2 AO/EB double fluorescent staining assay was used to observe cell apoptosis. The results showed the apoptotic cells appeared in the cell Juglone-treated groups. Normal cells had a regular nuclear with green fluorimetric stain, while apoptotic cell had unregular nuclear with yellowish green stain and the capacity of cell became smaller.
1.2.2 Detect apoptosis by flow cytometry
1.2.2.1 PI staining assay was used to detect apoptosis. The results showed that the percentage of apoptotic cells was increased significantly from 0.16±0.04% to 28.42±4.76%.
1.2.2.2 Annexin V-FITC/PI double staining was used to detect cell apoptosis. The results showed that the percentage of apoptotic cells was increased significantly from 9.44±3.48% to 71.96±5.26%.
2 Molecular mechanism of apoptosis induced by Juglone in HL-60 cell
2.1 The effect of Juglone on the mitochondrial function
2.1.1 The effect of Juglone on the mitochondrial transmembrane potential (ΔΨm) The results showed thatΔΨm was decreased.
2.1.2 The effect of Juglone on the apoptotosis-related proteins expression
2.1.2.1 The effect of Juglone on the Bcl-2 and Bax
The results showed that Bax protein and gene expression was increased and Bcl-2 protein and gene expression was decreased. The ratio of Bax/Bcl-2 was increased. Results indicated that apoptosis induced by Juglone involved the changes of Bcl-2 family.
2.1.2.2 The effect of Juglone on the Cyt C, Smac and AIF proteins
The results showed that Juglone could increase the release Cyt C, Smac and AIF proteins from mitochondrion to cytoplasm in a dose- and time-dependent manner.
2.1.2.3 The effect of Juglone on the caspase-3, -9, PARP proteins expression and activity of caspase.
The results showed that procaspase-3 and procaspase-9 were cut and PARP substrate of caspase was decomposed along with the elevating of concentration. The activities of caspase-3, -9 were also increased in a dose- and time-dependent manner.
2.2 The effect of ROS on the apoptosis induced by Juglone in HL-60 cell
2.2.1 The effect of Juglone on ROS
The results showed that the ROS increased significantly with concentration 1.0 and 1.5μg/mL compared with control group. It indicated that the ROS could be increased by Juglone in HL-60 cells.
2.2.2 The effect of Juglone on GSH
Results showed that the content of GSH was significantly decreased. It indicated that Juglone could induce oxidative stress in HL-60 cells.
2.2.3 The effect of NAC on the apoptosis induced by Juglone in HL-60 cell
The results showed that the percentage of apoptotic cells was 6.85±1.89%, 7.71±2.54%, 82.26±10.85% and11.67±3.26%, respectively. It indicated that NAC could inhibit the apoptosis induced by Juglone.
2.2.4 The effect of NAC on the apoptotosis-related proteins expression
2.2.4.1 The effect of NAC on the Bcl-2 and Bax proteins expression
The results showed that NAC had no obviously effect on Bcl-2 and Bax proteins expression. Julgone could increase Bax protein expression and decrease Bcl-2 protein expression. The ratio of Bax/Bcl-2 was increased, While NAC could inhibit the procession.
2.2.4.2 The effect of NAC on the Cyt C and Smac proteins
The results showed that NAC had no obviously on Cyt C and Smac proteins. Juglone could increase the Cyt C and Smac protein releasing to cytoplasm, While NAC could inhibit the procession.
2.2.4.3 The effect of NAC on the caspase-3, -9 proteins expression
The results showed that NAC had no obviously effect on the procaspase-3 and procaspase-9 protein expression. Juglone could promote the procaspase-3 and procaspase-9 to cutting, while the NAC could inhibit the procession.
2.3 The effect of Juglone on the MAPK pathway
The results showed that Juglone had no obviously effect on the p38 and JNK protein levels. But Juglone promoted an increase of p-ERK in a dose dependent way. It suggested that the ERK involved in the apoptosis induced by Juglone.
2.4 The effect of Juglone on the PI3K/AKT pathway
The results showed that Juglone could induce a significant decrease p-AKT at 0.5μg/mL, p-AKT expression was inhibited by Juglone. It suggested that PI3K/AKT pathway involved in the apoptosis induced by Juglone.
Conclusion:
1. Juglone could inhibit the cell proliferation in a dose- and time-dependent manner.
2. Juglone could induce apoptosis in HL-60 cell.
3. Juglone could induce apoptosis through mitochondrial pathway in HL-60 cell.
4. Juglone could increase the ROS in HL-60 cells and activate the mitochondrial pathway to induce apoptosis.
5. Juglone could activate ERK pathway and inhibit PI3K/AKT pathway.
引文
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