PKCα在Ⅶa-TF/PAR2促进SW620细胞增殖、迁移与生存中的作用探讨
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摘要
目的：在结肠癌SW620细胞系中,探讨protein kinase Cα (PKCα)在TF-Ⅶa-PAR2信号转导轴中是否被激活以及其在结肠癌细胞株增殖、迁移与生存中的作用；进一步分析该过程中PKCa的下游信号分子及其调控的效应分子,以阐明TF-Ⅶa-PAR2-PKCa促进SW620细胞增殖、迁移与生存的分子机制。
方法：(1)采用因子Ⅶa (10nM)、PAR2激动剂(PAR2-AP,100μM)以及PKC激动剂佛波酯(PMA,100nM)等处理SW620细胞不同时间,western blot检测其PKCα与p-PKCα的表达,免疫荧光试验观察PKCα的分布情况。(2)借助抑制抗体(α-TF、α-PAR2)同型对照抗体(mopc-21)、PKCα抑制剂(safingol,10μM)及ERK1/2抑制剂(U0126,10μM)进行抑制试验,western blot检测其PKCα与p-PKCα, ERK1/2与p-ERK1/2以及NF-κB与P-NF-κB的表达,探讨PKCα_上下游的信号分子。(3)采用PMA(100nM), Ⅶa (10nM)及PKCα印制剂(safingol,10μM)等不同组合刺激SW620细胞后,MTT探测细胞增殖能力,Transwell试验检测细胞迁移潜能,流式细胞术(FCM)评估细胞的生存能力。(4)采用Ⅶa (10nM) PKCα抑制剂(safingol,10μM)以及NF-κB抑制剂(PDTC,5μM)等不同组合刺激SW620细胞后,实时荧光定量PCR与western blot检测MMP-9, caspase-3, TF,与Bcl-2/Bax的表达,TF活性检测试剂盒检测TF活性。
结果：(1)与]medium组比较,Ⅶa (10nM)、PAR2-AP (100μM)及PMA (100nM)均能明显促进PKCα的磷酸化,而对PKCα的表达没有显著性影响。免疫荧光结果表明,medium组PKCα主要分布在胞浆,分布无明显规律,核内未探测到PKCα的表达；Ⅶα、 PAR2-AP、PMA处理组的PKCα主要分布在核周,并且核内亦有少量表达。(2)与medium组比较,抗TF或抗PAR2抗体均能明显减弱Ⅶa与PAR2-AP诱导的p-PKCα的表达(p<0.05),而同型对照抗体(mopc-21)则没有这种抑制效果(P>0.05)。与Ⅶa处理组比较,PKCα抑制剂(safingol,10μM)能显著抑制Ⅶa对下游信号分子ERK1/2及NF-κB的磷酸化(p<0.05)。(3)与medium组比较,Ⅶa (10nM)及PMA (100nM)均能明显促进细胞的增殖、迁移与生存(p<0.05)；这一促进增强作用能被PKCα印制剂(safingol,10μM)阻断(p<0.05)。(4)与medium组比较,Ⅶa (10nM)能诱导caspase-3与Bax表达明显下调,MMP-9、TF与Bcl-2表达以及TF活性明显上调,这一诱导作用能被PKCα抑制剂(safingol,10μM)与NF-κB抑制剂(PDTC,5μM)阴断(p<0.05)
结论：(1)在结肠癌细胞株SW620中,PKCα能够被因子Ⅶa与PAR2-AP激活。
(2)Ⅶa依赖TF及PAR2激活PKCα,进而活化下游的ERK1/2与NF-KB。
(3)PKCα激活对于因子Ⅶa促进SW620细胞的增殖、迁移与生存是非常必要的。
(4)PKCα激活参与了因子VIIa诱导的MMP-9、caspase-3、TF与Bcl-2/Bax效应分子表达。
Objective:To explore whether the protein kinase Ca (PKCa) is activated in the TF-VIIa-PAR2signal transduction axis as well as its roles in the proliferation, migration and survival of colon cancer cell lines SW620, and to further analyze upstream and downstream signaling molecules of PKCa and its regulation of effector molecules in the process to clarify the underlying molecular mechanism that TF-VIIa-PAR2-PKCa promotes SW620cell proliferation, migration, and survival.
Methods:(1) SW620cells were treated with factor Ⅶa (10nM), protease activated receptor-2agonists (PAR2-AP,100μM), phorbol-12-myristate-13-acetate (PMA,100nM) and medium for different times, and the expression of PKC a and p-PKC a was detected by Western blot, and meanwhile the distribution of PKC a was observed by immunofluorescence assay, respectively.(2) With inhibition antibody (a-TF, a-PAR2), isotype control antibody (mopc-21), PKC a inhibitor (safingol,10μM) and ERK1/2inhibitor (U0126,10μM), inhibition experiments were carried out and western blot was used to detect the expression of PKCa and p-PKCa, ERK1/2and p-ERK1/2as well as NF-κB and p-NF-KB, so as to explore upstream and downstream signaling molecules of PKCa.(3) After SW620cells were treated with different combinations of PMA (100nM), Ⅶa (10nM) and PKC a inhibitor(safingol,10μM), the cell proliferation ability was detected by MTT assay, the cell migratory potential was tested by transwell experiment and the cell survival ability was assessed by flow cytometry.(4) After SW620cells were treated with different combinations of VIIa(10nM), PKC α inhibitor(safingol,10μM) and NF-κB inhibitor (PDTC,5μM), real-time fluorescence quantitative PCR and western blot were used to detect the expression of MMP-9, caspase-3, TF, and Bcl-2/Bax, and TF activity kits was used to detect TF activity.
Results:(1) Compared with the medium group,Ⅶa (10nM), PAR2-AP (100μM) and PMA (100nM, positive control) could obviously induced phosphorylation of PKCα (p-PKCα) but did not affect the expression of total PKCα. Immunofluorescence results showed that PKCα was distributed mostly in the cytoplasm with irregularity but not detected in the nucleus in untreated cells; while in the Ⅶa or PAR2-AP or PMA treated cells, PKCα was mainly localized in the perinuclear region with slight distribution in the nucleus.(2) Compared with the medium group, α-TF or α-PAR2could dramatically attenuate phosphorylation of PKCα (p-PKCα) induced by Ⅶa (p<0.05, compared to Ⅶa treatment alone), which was not found in pretreatment with isotype control antibody (Mopc-21). Compared with the Ⅶa treatment alone group, PKCα inhibitor (safingol,10μM) significantly inhibited Ⅶa-induced downstream signaling molecules ERK1/2and NF-κB phosphorylation (p<0.05).(3) The cell proliferation ability, migratory potential and survival ability were significantly enhanced by stimulation with Vila or PMA (p<0.05, compared to medium control). However, the enhanced effects by Vila or PMA on cell proliferation, migration and survival were blocked by safingol (p<0.05, compared to Vila or PMA treatment alone).(4) Compared with the medium group, obvious downregulation of caspase-3and Bax expression and significant upregulation of MMP-9, TF and Bcl-2expression as well as TF activity were elicited by Vila (p<0.05). However, the induced effects by Vila were dramatically neutralized by safingol or PDTC treatment (p<0.05, compared to Vila treatment alone).
Conclusions:
(1) Activation of PKCa can be caused by PAR2-AP and Vila in SW620cells.
(2) Ⅶa-induced PKCa activation is dependent on TF and PAR2, and consequently activates downstream of ERK1/2and NF-κB.
(3) PKCa activation is necessary for the proliferation, migration and survival of SW620cells stimulated by Ⅶa.
(4) PKCa activation is involved in the expression of MMP-9, caspase-3, TF, and Bcl-2/Bax induced by Vila.
方法：(1)采用因子Ⅶa (10nM)、PAR2激动剂(PAR2-AP,100μM)以及PKC激动剂佛波酯(PMA,100nM)等处理SW620细胞不同时间,western blot检测其PKCα与p-PKCα的表达,免疫荧光试验观察PKCα的分布情况。(2)借助抑制抗体(α-TF、α-PAR2)同型对照抗体(mopc-21)、PKCα抑制剂(safingol,10μM)及ERK1/2抑制剂(U0126,10μM)进行抑制试验,western blot检测其PKCα与p-PKCα, ERK1/2与p-ERK1/2以及NF-κB与P-NF-κB的表达,探讨PKCα_上下游的信号分子。(3)采用PMA(100nM), Ⅶa (10nM)及PKCα印制剂(safingol,10μM)等不同组合刺激SW620细胞后,MTT探测细胞增殖能力,Transwell试验检测细胞迁移潜能,流式细胞术(FCM)评估细胞的生存能力。(4)采用Ⅶa (10nM) PKCα抑制剂(safingol,10μM)以及NF-κB抑制剂(PDTC,5μM)等不同组合刺激SW620细胞后,实时荧光定量PCR与western blot检测MMP-9, caspase-3, TF,与Bcl-2/Bax的表达,TF活性检测试剂盒检测TF活性。
结果：(1)与]medium组比较,Ⅶa (10nM)、PAR2-AP (100μM)及PMA (100nM)均能明显促进PKCα的磷酸化,而对PKCα的表达没有显著性影响。免疫荧光结果表明,medium组PKCα主要分布在胞浆,分布无明显规律,核内未探测到PKCα的表达；Ⅶα、 PAR2-AP、PMA处理组的PKCα主要分布在核周,并且核内亦有少量表达。(2)与medium组比较,抗TF或抗PAR2抗体均能明显减弱Ⅶa与PAR2-AP诱导的p-PKCα的表达(p<0.05),而同型对照抗体(mopc-21)则没有这种抑制效果(P>0.05)。与Ⅶa处理组比较,PKCα抑制剂(safingol,10μM)能显著抑制Ⅶa对下游信号分子ERK1/2及NF-κB的磷酸化(p<0.05)。(3)与medium组比较,Ⅶa (10nM)及PMA (100nM)均能明显促进细胞的增殖、迁移与生存(p<0.05)；这一促进增强作用能被PKCα印制剂(safingol,10μM)阻断(p<0.05)。(4)与medium组比较,Ⅶa (10nM)能诱导caspase-3与Bax表达明显下调,MMP-9、TF与Bcl-2表达以及TF活性明显上调,这一诱导作用能被PKCα抑制剂(safingol,10μM)与NF-κB抑制剂(PDTC,5μM)阴断(p<0.05)
结论：(1)在结肠癌细胞株SW620中,PKCα能够被因子Ⅶa与PAR2-AP激活。
(2)Ⅶa依赖TF及PAR2激活PKCα,进而活化下游的ERK1/2与NF-KB。
(3)PKCα激活对于因子Ⅶa促进SW620细胞的增殖、迁移与生存是非常必要的。
(4)PKCα激活参与了因子VIIa诱导的MMP-9、caspase-3、TF与Bcl-2/Bax效应分子表达。
Objective:To explore whether the protein kinase Ca (PKCa) is activated in the TF-VIIa-PAR2signal transduction axis as well as its roles in the proliferation, migration and survival of colon cancer cell lines SW620, and to further analyze upstream and downstream signaling molecules of PKCa and its regulation of effector molecules in the process to clarify the underlying molecular mechanism that TF-VIIa-PAR2-PKCa promotes SW620cell proliferation, migration, and survival.
Methods:(1) SW620cells were treated with factor Ⅶa (10nM), protease activated receptor-2agonists (PAR2-AP,100μM), phorbol-12-myristate-13-acetate (PMA,100nM) and medium for different times, and the expression of PKC a and p-PKC a was detected by Western blot, and meanwhile the distribution of PKC a was observed by immunofluorescence assay, respectively.(2) With inhibition antibody (a-TF, a-PAR2), isotype control antibody (mopc-21), PKC a inhibitor (safingol,10μM) and ERK1/2inhibitor (U0126,10μM), inhibition experiments were carried out and western blot was used to detect the expression of PKCa and p-PKCa, ERK1/2and p-ERK1/2as well as NF-κB and p-NF-KB, so as to explore upstream and downstream signaling molecules of PKCa.(3) After SW620cells were treated with different combinations of PMA (100nM), Ⅶa (10nM) and PKC a inhibitor(safingol,10μM), the cell proliferation ability was detected by MTT assay, the cell migratory potential was tested by transwell experiment and the cell survival ability was assessed by flow cytometry.(4) After SW620cells were treated with different combinations of VIIa(10nM), PKC α inhibitor(safingol,10μM) and NF-κB inhibitor (PDTC,5μM), real-time fluorescence quantitative PCR and western blot were used to detect the expression of MMP-9, caspase-3, TF, and Bcl-2/Bax, and TF activity kits was used to detect TF activity.
Results:(1) Compared with the medium group,Ⅶa (10nM), PAR2-AP (100μM) and PMA (100nM, positive control) could obviously induced phosphorylation of PKCα (p-PKCα) but did not affect the expression of total PKCα. Immunofluorescence results showed that PKCα was distributed mostly in the cytoplasm with irregularity but not detected in the nucleus in untreated cells; while in the Ⅶa or PAR2-AP or PMA treated cells, PKCα was mainly localized in the perinuclear region with slight distribution in the nucleus.(2) Compared with the medium group, α-TF or α-PAR2could dramatically attenuate phosphorylation of PKCα (p-PKCα) induced by Ⅶa (p<0.05, compared to Ⅶa treatment alone), which was not found in pretreatment with isotype control antibody (Mopc-21). Compared with the Ⅶa treatment alone group, PKCα inhibitor (safingol,10μM) significantly inhibited Ⅶa-induced downstream signaling molecules ERK1/2and NF-κB phosphorylation (p<0.05).(3) The cell proliferation ability, migratory potential and survival ability were significantly enhanced by stimulation with Vila or PMA (p<0.05, compared to medium control). However, the enhanced effects by Vila or PMA on cell proliferation, migration and survival were blocked by safingol (p<0.05, compared to Vila or PMA treatment alone).(4) Compared with the medium group, obvious downregulation of caspase-3and Bax expression and significant upregulation of MMP-9, TF and Bcl-2expression as well as TF activity were elicited by Vila (p<0.05). However, the induced effects by Vila were dramatically neutralized by safingol or PDTC treatment (p<0.05, compared to Vila treatment alone).
Conclusions:
(1) Activation of PKCa can be caused by PAR2-AP and Vila in SW620cells.
(2) Ⅶa-induced PKCa activation is dependent on TF and PAR2, and consequently activates downstream of ERK1/2and NF-κB.
(3) PKCa activation is necessary for the proliferation, migration and survival of SW620cells stimulated by Ⅶa.
(4) PKCa activation is involved in the expression of MMP-9, caspase-3, TF, and Bcl-2/Bax induced by Vila.
引文
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