褪黑素在自噬介导的小鼠肝癌H22细胞存活中的作用
摘要
褪黑素（Melatonin，MT）是一种由人脑松果体合成的吲哚类化合物。具有重要的生理和病理功能，能够调节人体的昼夜节律性和季节节律性，具有调节机体免疫反应、体重、生殖、调整时差、肿瘤生长抑制等功能，还可以作为还原剂起到清除自由基、抗氧化的作用，有助于延缓衰老。褪黑素可以通过受体MT1和MT2对多种癌症具有抗增殖效果，如乳腺癌、肺癌、转移性肾细胞癌、肝癌、恶性肿瘤的脑转移、卵巢癌、神经母细胞瘤、膀胱癌、白血病等。
细胞的自噬功能有助于细胞清除过量的、有害的、半衰期较长的蛋白或细胞器，从而为必须的细胞组分提供保护，为细胞的重建、再生和修复提供必须原料，实现细胞的再循环和再利用。细胞中的自噬可以通过多条信号通路与癌症密切相关，如PI3K/Akt/mTOR信号通路、LKB1/AMPK/mTOR信号通路、p53信号通路、BCL-2通路、内质网应激和钙离子通路等。褪黑素具有抗肿瘤效果，也能够调节细胞的自噬过程，这一过程可能是通过调控mTOR或Beclin-1介导的自噬信号通路实现的。但是褪黑素是否在细胞自噬诱导的肿瘤抑制机制或细胞保护机制中起作用尚不明确。因此，本研究对褪黑素在小鼠肝癌H22细胞自噬相关信号通路中的作用进行了研究。目的：探讨褪黑素对H22荷瘤小鼠肿瘤模型的抑制效果，研究褪黑素对小鼠肿瘤细胞自噬信号通路的影响及阻断细胞自噬过程对褪黑素诱导肿瘤细胞凋亡影响，期望能够揭示褪黑素通过调节细胞自噬通路发挥抗肿瘤效果的机制。
方法：
1、采用BALB/c小鼠30只，将H22细胞以皮下方式接种到小鼠的右侧腋部，每只接种细胞数量分别为1×106细胞/100μL。随机将其分为生理盐水组、10mg/kg（MLT）处理组和20mg/kg（MLT）处理组开始治疗，每天腹腔注射一次，连续14天，每隔3天用游标卡尺测量一次肿瘤的长和宽，采用下列公式计算肿瘤的体积，即肿瘤体积（mm3）=0.52×长×宽2。第15天处死小鼠，称取小鼠肿瘤的重量，并采用方差分析对其进行统计学计算。
2、通过透射电镜观察褪黑素处理后肿瘤细胞中自噬泡的形成；蛋白免疫印记法检测自噬标志性蛋白Beclin-1的表达和自噬标志物LC3-Ⅰ向LC3-Ⅱ的转换及Akt/mTOR信号通路的抑制；荧光染色免疫组织化学方法检测LC3分子表达。
3、体外实验采用慢病毒载体Beclin-1shRNA敲减H22细胞Beclin-1表达，以及自噬特异性阻断剂3-甲基腺嘌呤（3-methyladenine，3-MA）阻断H22细胞自噬通路。采用细胞活性测定法（MTT法）检测自噬通路阻断后褪黑素对细胞存活的影响。流式细胞仪检测自噬通路阻断后褪黑素对细胞凋亡的影响。
结果：
1、成功建立H22荷瘤小鼠模型。在褪黑素处理组中，小鼠肿瘤的重量明显降低；褪黑素处理组肿瘤的体积也显著降低，且具有一定的量效关系。在解剖时我们发现，对照组荷瘤小鼠的肿瘤包膜很不完整，基部比较宽，导致肿瘤组织不容易剥离，而褪黑素处理组小鼠的肿瘤体积变小，包膜比较完整，很容易剥离，这充分说明褪黑素具有抗肿瘤功能，能够限制肿瘤的生长，并且这种抑制作用具有剂量依赖性。
2、经褪黑素处理的H22荷瘤小鼠的肿瘤组织Beclin-1表达下降，LC3-Ⅱ/LC3-Ⅰ比值升高。本研究首次证明了褪黑素能够在H22荷瘤小鼠模型体内促进自噬，增加自噬相关的蛋白表达，诱导自噬相关的形态学变化。我们的研究还表明，褪黑素抑制Akt和mTOR的磷酸化。这证明，褪黑素可在H22荷瘤小鼠体内促进细胞自噬过程可能与其对PI3K/Akt/mTOR信号通路的调节有关。
3、通过对Ⅲ型PI3K信号通路的抑制，3-MA阻止了自噬反应，并且在培养的H22细胞系中，减弱了褪黑素所抑制的H22细胞增殖功能，同时促进了褪黑素诱导的H22细胞凋亡。通过敲减Beclin-1的表达抑制自噬，减少了褪黑素抑制的H22细胞增殖功能，同时促进了褪黑素诱导的细胞凋亡。这些数据表明，通过作用于III型PI3K/Beclin-1信号通路，褪黑素可以激活保护性自噬反应以适应严峻的环境，并保护H22肝癌细胞免于死亡。对保护性自噬的抑制可以提高褪黑素抗肿瘤作用。另外，治疗药物结合自噬抑制剂可能具有抑制肿瘤发展的协同作用。这项研究阐明了细胞凋亡和褪黑素诱导的自噬之间的联系，为相关癌症临床治疗策略的完善提供了参考依据。
结论：
1、成功建立肝癌H22荷瘤小鼠模型，发现采用褪黑素处理能够明显降低肿瘤重量和体积，这说明褪黑素可能具有良好的抗肿瘤效果。
2、证实了褪黑素在H22荷瘤小鼠中诱导自噬，能够诱导自噬过程标志蛋白Beclin-1和LC-3的表达，进而抑制H22荷瘤小鼠中的Akt/mTOR信号通路。
3、褪黑素可以激活H22细胞保护性自噬反应。通过Beclin-1敲减或3-MA阻断褪黑素诱导的自噬通路，可以抑制H22细胞增殖，并且促进细胞的凋亡，提示抑制褪黑素诱导的保护性自噬通路可以提高褪黑素抗肿瘤作用
Melatonin (MLT) is a kind of indole secreted by human pineal glands. It has manyimportant physiological and pathological functions, including regulating sleep and circadianrhythms, preventing mutagenesis, oxidation, providing cardiovascular protection, modulatingimmune, controlling reproduction, regulating mental disorders and delay aging etc. Actingthrough its receptors MT1and MT2, MLT could exert effects of anti-proliferation on manykinds caners, containing beast cancer, lung caner, endometrial, prostate cancers, melanoma,hepatoma, and colon. Autophagy contributes to eliminate overexpressed, toxic, and long-termproteins or organelles, protecting essential cellular components. In cancer cells, autophagicresponses have the same signaling pathway with normal physiological status, whileautophagic pathway is more complicated because of some impairments of the sharedPI3K/Akt/mTOR signaling pathway and various interactions with other pathways. Autophagyis related to cancer through several signaling pathways including PI3K/Akt/mTOR, LKB1/AMPK/mTOR, p53, BCL-2, endoplasmic reticulum stress, and Calcium channel. MLT canenhance cellular autophagic process, while its effects don’t act on the autophagic process, buton its inducible factors. Inducing autophagy by MLE may be through activation of mTOR orBeclin-1.
Objective To investigate roles of MLT on inducing autophagy in cancers.
Methods The model of H22tumor in BALB/c mice was established. Briefly, micewere subcutaneously injected0.1mL of cell suspensions containing1.0×106cells/ml in thedorsal area. After inoculation with H22cells on day0, mice were randomly assigned intothree groups (n=10for each group). Tumor-bearing mice were given an intraperitonealinjection with MLT (10,20mg/kg per day for14days) or sterile normal saline (0.2mL perday for14days). Tumor size was determined by caliper measurement of the largest andperpendicular diameters every3days. Tumor volumes were calculated according to theformula: V=a×b2×0.52, where a is the largest superficial diameter and b is the smallest superficial diameter. On day15, mice were sacrificed; tumors were dissected and weighed. Todetect the Beclin1and LC3expression, tumors tissues excised were fixed in10%formalin orfrozen in80°C. The Beclin-1, LC3expression and Akt phosphorylation was detected byWestern-Blot and Immunofluorescence. The apoptosis of H22cells was detected by flowcytometry. The formation of autophagic vacuoles was further assessed and confirmed bytransmission electron microscopic test. To inhibit autophagy, H22cells were pretreated withBeclin-1RNAi(LV-control, or LV-shbeclin-1) prior to administration of MLT(100μM) orco-treated with MLT(100μM) and3-MA(10mmol/L).
Results First, tumor volume was more suppressed in MLT-treated groups than salinecontrol. It was clear that MLT-treated mice showed significant inhibition to the tumor growth.
Second, we demonstrated that MLT could induce autophagy in H22-bearing mice,promote expression of Beclin-1and LC-3, and inhibit Akt/mTOR-mediated signaling pathway.Only a few LC3-positive puncta were observed in tumor tissue from saline-treatedH22-bearing mice. However, in the tumor tissue from MTL-treated H22-bearing mice, LC3punctuated staining was increased. In contrast to saline-treated H22-bearing mice,MLT-treated animals showed increased autophagic morphology, such as autophagic vacuolesin the cytoplasm. These results indicate that MLT induced autophagic formation.
Finally, we studied effects of blocking autophagic pathways on inducing autophagy byMLT. To identify whether the role of MLT-induced autophagy in hepatoma cells is aprotective or death promoting mechanism, we evaluated the consequences of the disruption ofautophagy by treatment with Beclin-1RNAi or3-MA (an inhibitor of autophagy) on theanti-tumor effects of MLT. Our results show that the level of Beclin-1was significantlydecreased by Beclin-1RNAi. Compared with LV-control, Beclin-1RNAi decreasedMLT-inhibited cell viability and enhanced MLT-induced apoptosis. Further studies showedthat co-treatment with MLT (100μM) and3-MA(10mmol/L) significantly decreased cellviability, compared with treatment with MLT alone. Co-treatment with MLT and3-MA alsosignificantly increased the apoptotic population, especially late apoptotic cells, compared withthecells treated with MLT alone.
Conclusion The model of H22tumor BALB/c mice was established and anti-tumorefficacy of MLT was directly observed in tumors excised from H22-bearing mice. MLT couldinduce autophagy in H22-bearing mice, promote expression of Beclin-1and LC-3, and inhibit Akt/mTOR-mediated signaling pathway. Induction of autophagy was associated withinhibition of the PI3K/Akt/mTOR signaling pathway. Furthermore, the disruption of theautophagic process enhances the biological effects of melatonin in H22cells in vitro.
细胞的自噬功能有助于细胞清除过量的、有害的、半衰期较长的蛋白或细胞器，从而为必须的细胞组分提供保护，为细胞的重建、再生和修复提供必须原料，实现细胞的再循环和再利用。细胞中的自噬可以通过多条信号通路与癌症密切相关，如PI3K/Akt/mTOR信号通路、LKB1/AMPK/mTOR信号通路、p53信号通路、BCL-2通路、内质网应激和钙离子通路等。褪黑素具有抗肿瘤效果，也能够调节细胞的自噬过程，这一过程可能是通过调控mTOR或Beclin-1介导的自噬信号通路实现的。但是褪黑素是否在细胞自噬诱导的肿瘤抑制机制或细胞保护机制中起作用尚不明确。因此，本研究对褪黑素在小鼠肝癌H22细胞自噬相关信号通路中的作用进行了研究。目的：探讨褪黑素对H22荷瘤小鼠肿瘤模型的抑制效果，研究褪黑素对小鼠肿瘤细胞自噬信号通路的影响及阻断细胞自噬过程对褪黑素诱导肿瘤细胞凋亡影响，期望能够揭示褪黑素通过调节细胞自噬通路发挥抗肿瘤效果的机制。
方法：
1、采用BALB/c小鼠30只，将H22细胞以皮下方式接种到小鼠的右侧腋部，每只接种细胞数量分别为1×106细胞/100μL。随机将其分为生理盐水组、10mg/kg（MLT）处理组和20mg/kg（MLT）处理组开始治疗，每天腹腔注射一次，连续14天，每隔3天用游标卡尺测量一次肿瘤的长和宽，采用下列公式计算肿瘤的体积，即肿瘤体积（mm3）=0.52×长×宽2。第15天处死小鼠，称取小鼠肿瘤的重量，并采用方差分析对其进行统计学计算。
2、通过透射电镜观察褪黑素处理后肿瘤细胞中自噬泡的形成；蛋白免疫印记法检测自噬标志性蛋白Beclin-1的表达和自噬标志物LC3-Ⅰ向LC3-Ⅱ的转换及Akt/mTOR信号通路的抑制；荧光染色免疫组织化学方法检测LC3分子表达。
3、体外实验采用慢病毒载体Beclin-1shRNA敲减H22细胞Beclin-1表达，以及自噬特异性阻断剂3-甲基腺嘌呤（3-methyladenine，3-MA）阻断H22细胞自噬通路。采用细胞活性测定法（MTT法）检测自噬通路阻断后褪黑素对细胞存活的影响。流式细胞仪检测自噬通路阻断后褪黑素对细胞凋亡的影响。
结果：
1、成功建立H22荷瘤小鼠模型。在褪黑素处理组中，小鼠肿瘤的重量明显降低；褪黑素处理组肿瘤的体积也显著降低，且具有一定的量效关系。在解剖时我们发现，对照组荷瘤小鼠的肿瘤包膜很不完整，基部比较宽，导致肿瘤组织不容易剥离，而褪黑素处理组小鼠的肿瘤体积变小，包膜比较完整，很容易剥离，这充分说明褪黑素具有抗肿瘤功能，能够限制肿瘤的生长，并且这种抑制作用具有剂量依赖性。
2、经褪黑素处理的H22荷瘤小鼠的肿瘤组织Beclin-1表达下降，LC3-Ⅱ/LC3-Ⅰ比值升高。本研究首次证明了褪黑素能够在H22荷瘤小鼠模型体内促进自噬，增加自噬相关的蛋白表达，诱导自噬相关的形态学变化。我们的研究还表明，褪黑素抑制Akt和mTOR的磷酸化。这证明，褪黑素可在H22荷瘤小鼠体内促进细胞自噬过程可能与其对PI3K/Akt/mTOR信号通路的调节有关。
3、通过对Ⅲ型PI3K信号通路的抑制，3-MA阻止了自噬反应，并且在培养的H22细胞系中，减弱了褪黑素所抑制的H22细胞增殖功能，同时促进了褪黑素诱导的H22细胞凋亡。通过敲减Beclin-1的表达抑制自噬，减少了褪黑素抑制的H22细胞增殖功能，同时促进了褪黑素诱导的细胞凋亡。这些数据表明，通过作用于III型PI3K/Beclin-1信号通路，褪黑素可以激活保护性自噬反应以适应严峻的环境，并保护H22肝癌细胞免于死亡。对保护性自噬的抑制可以提高褪黑素抗肿瘤作用。另外，治疗药物结合自噬抑制剂可能具有抑制肿瘤发展的协同作用。这项研究阐明了细胞凋亡和褪黑素诱导的自噬之间的联系，为相关癌症临床治疗策略的完善提供了参考依据。
结论：
1、成功建立肝癌H22荷瘤小鼠模型，发现采用褪黑素处理能够明显降低肿瘤重量和体积，这说明褪黑素可能具有良好的抗肿瘤效果。
2、证实了褪黑素在H22荷瘤小鼠中诱导自噬，能够诱导自噬过程标志蛋白Beclin-1和LC-3的表达，进而抑制H22荷瘤小鼠中的Akt/mTOR信号通路。
3、褪黑素可以激活H22细胞保护性自噬反应。通过Beclin-1敲减或3-MA阻断褪黑素诱导的自噬通路，可以抑制H22细胞增殖，并且促进细胞的凋亡，提示抑制褪黑素诱导的保护性自噬通路可以提高褪黑素抗肿瘤作用
Melatonin (MLT) is a kind of indole secreted by human pineal glands. It has manyimportant physiological and pathological functions, including regulating sleep and circadianrhythms, preventing mutagenesis, oxidation, providing cardiovascular protection, modulatingimmune, controlling reproduction, regulating mental disorders and delay aging etc. Actingthrough its receptors MT1and MT2, MLT could exert effects of anti-proliferation on manykinds caners, containing beast cancer, lung caner, endometrial, prostate cancers, melanoma,hepatoma, and colon. Autophagy contributes to eliminate overexpressed, toxic, and long-termproteins or organelles, protecting essential cellular components. In cancer cells, autophagicresponses have the same signaling pathway with normal physiological status, whileautophagic pathway is more complicated because of some impairments of the sharedPI3K/Akt/mTOR signaling pathway and various interactions with other pathways. Autophagyis related to cancer through several signaling pathways including PI3K/Akt/mTOR, LKB1/AMPK/mTOR, p53, BCL-2, endoplasmic reticulum stress, and Calcium channel. MLT canenhance cellular autophagic process, while its effects don’t act on the autophagic process, buton its inducible factors. Inducing autophagy by MLE may be through activation of mTOR orBeclin-1.
Objective To investigate roles of MLT on inducing autophagy in cancers.
Methods The model of H22tumor in BALB/c mice was established. Briefly, micewere subcutaneously injected0.1mL of cell suspensions containing1.0×106cells/ml in thedorsal area. After inoculation with H22cells on day0, mice were randomly assigned intothree groups (n=10for each group). Tumor-bearing mice were given an intraperitonealinjection with MLT (10,20mg/kg per day for14days) or sterile normal saline (0.2mL perday for14days). Tumor size was determined by caliper measurement of the largest andperpendicular diameters every3days. Tumor volumes were calculated according to theformula: V=a×b2×0.52, where a is the largest superficial diameter and b is the smallest superficial diameter. On day15, mice were sacrificed; tumors were dissected and weighed. Todetect the Beclin1and LC3expression, tumors tissues excised were fixed in10%formalin orfrozen in80°C. The Beclin-1, LC3expression and Akt phosphorylation was detected byWestern-Blot and Immunofluorescence. The apoptosis of H22cells was detected by flowcytometry. The formation of autophagic vacuoles was further assessed and confirmed bytransmission electron microscopic test. To inhibit autophagy, H22cells were pretreated withBeclin-1RNAi(LV-control, or LV-shbeclin-1) prior to administration of MLT(100μM) orco-treated with MLT(100μM) and3-MA(10mmol/L).
Results First, tumor volume was more suppressed in MLT-treated groups than salinecontrol. It was clear that MLT-treated mice showed significant inhibition to the tumor growth.
Second, we demonstrated that MLT could induce autophagy in H22-bearing mice,promote expression of Beclin-1and LC-3, and inhibit Akt/mTOR-mediated signaling pathway.Only a few LC3-positive puncta were observed in tumor tissue from saline-treatedH22-bearing mice. However, in the tumor tissue from MTL-treated H22-bearing mice, LC3punctuated staining was increased. In contrast to saline-treated H22-bearing mice,MLT-treated animals showed increased autophagic morphology, such as autophagic vacuolesin the cytoplasm. These results indicate that MLT induced autophagic formation.
Finally, we studied effects of blocking autophagic pathways on inducing autophagy byMLT. To identify whether the role of MLT-induced autophagy in hepatoma cells is aprotective or death promoting mechanism, we evaluated the consequences of the disruption ofautophagy by treatment with Beclin-1RNAi or3-MA (an inhibitor of autophagy) on theanti-tumor effects of MLT. Our results show that the level of Beclin-1was significantlydecreased by Beclin-1RNAi. Compared with LV-control, Beclin-1RNAi decreasedMLT-inhibited cell viability and enhanced MLT-induced apoptosis. Further studies showedthat co-treatment with MLT (100μM) and3-MA(10mmol/L) significantly decreased cellviability, compared with treatment with MLT alone. Co-treatment with MLT and3-MA alsosignificantly increased the apoptotic population, especially late apoptotic cells, compared withthecells treated with MLT alone.
Conclusion The model of H22tumor BALB/c mice was established and anti-tumorefficacy of MLT was directly observed in tumors excised from H22-bearing mice. MLT couldinduce autophagy in H22-bearing mice, promote expression of Beclin-1and LC-3, and inhibit Akt/mTOR-mediated signaling pathway. Induction of autophagy was associated withinhibition of the PI3K/Akt/mTOR signaling pathway. Furthermore, the disruption of theautophagic process enhances the biological effects of melatonin in H22cells in vitro.
引文
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