中枢CRF受体对可卡因戒断及外周CRF受体对前列腺癌细胞凋亡的影响
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摘要
促肾上腺皮质激素释放激素(corticotropin-releasingfactor,CRF)相关肽及其受体广泛分布于中枢和外周,并具有多种生物学效应。然而,其在中枢神经系统和外周的作用截然不同,甚至有时起到相反的作用。因此,研究CRF相关肽分别在中枢和外周的作用及其机制有着重要的意义。CRF相关肽具有调节应激行为、情绪活动、食物摄取及药物成瘾等作用,并且通过HPA轴发挥抑制炎症的作用。而在外周,CRF相关肽可保护心血管系统、促进炎症反应,并对代谢以及肿瘤生长有明显的影响。
在中枢的皮质纹状体及外周的前列腺癌组织中均有大量的CRF相关肽及其受体的表达,但其对可卡因戒断情况下皮质纹状体通路突触可塑性和前列腺癌细胞凋亡的作用尚未完全明了。本文研究发现:在中枢系统中,CRF能增强可卡因戒断情况下大鼠皮质纹状体神经通路LTP,且不同亚型受体具有不同作用:CRF激活CRFR1均能增强生理和可卡因戒断病理情况下大鼠皮质纹状体神经通路LTP,而激活CRFR2只增强可卡因戒断大鼠的皮质纹状体神经通路LTP。在外周,CRF通过CRFR1,调节Bax/Bcl-2比例从而促进小鼠RM-1前列癌细胞凋亡。同时,UCN2却通过CRFR2磷酸化Akt和CREB,上调Bcl-2,下调Bax表达,最终抑制RM-1细胞凋亡。
综上所述,本实验首次研究CRF相关肽及其受体对可卡因戒断大鼠的皮质纹状体神经通路LTP及对小鼠RM-1前列腺癌细胞凋亡的作用及机制,从一个侧面初步阐述了CRF受体在中枢和外周的不同作用。
第一部分CRF相关肽及其受体对可卡因戒断大鼠的皮质纹状体神经通路LTP的影响
同其它成瘾药物类似,可卡因滥用主要表现为长期滥用和高复吸率。在最近15年中,许多的研究证实下丘脑及下丘脑外CRF系统能影响可卡因滥用。可卡因成瘾过程中可能涉及类似于学习和记忆的机制,而这种机制需要皮质纹状体通路的参与。同时,皮质纹状体通路已经被广泛认为是习惯形成和存储的大脑中心。LTP是研究突触可塑性的重要实验模型。本文工作初步探讨了在可卡因戒断情况下,CRF受体的两种亚型对大鼠皮质纹状体突触可塑性的影响。实验结显示无论在可卡因戒断组还是在生理盐水组,CRF均呈剂量依赖性地增强大鼠皮质纹状体神经通路LTP。这一结果表明CRF相关肽可能会通过增强皮质纹状体神经通路LTP来导致复吸。在可卡因戒断组中,预先给予CRFR1选择性拮抗剂(NBI27914)或者CRFR2选择性拮抗剂(astression2B),CRF诱导增强的LTP均能被逆转;然而在生理盐水组中,CRF诱导增强的LTP只能被astression2B减弱。值得注意的是,外源性给予UCN2(CRFR2选择性激动剂)可以显著性增强可卡因戒断大鼠的皮质纹状体神经通路LTP,而对生理盐水组脑片的LTP没有影响;UCN2的LTP增强作用被astression2B完全阻断。综合本研究的实验结果,CRFR1在生理条件和可卡因戒断情况下均表达并发挥了增强大鼠皮质纹状体神经通路LTP,然而CRFR2只有在可卡因戒断情况下才发挥此作用。
综上所述,在可卡因戒断情况下,CRF相关肽能增加皮质纹状体神经通路LTP,而这一改变能促进应激导致的可卡因复吸。更重要的是,不同的CRF受体介导了不同的功能,其中CRFR1在生理和可卡因戒断病理情况下都能增强皮质纹状体神经通路LTP,而CRFR2只在可卡因戒断情况下参与调节神经适应性变化。这些研究结果提示CRFR2的功能在可卡因戒断后发生了明显改变,这种特异性变化可能是可卡因复吸的一个重要机制,有可能成为新的药物作用靶点来影响可卡因戒断后的复吸。
第二部分不同CRF受体对小鼠RM-1前列癌细胞凋亡的影响
CRF相关肽及其受体在外周的作用特别是对肿瘤的影响成为当前的研究热点。2002年,几位美国学者在人类前列腺癌标本中首次发现了UCN,然而有关CRFR的表达及其在前列腺癌细胞中的具体生理病理作用尚未报导。本文第二部分主要探讨了CRFRs在小鼠RM-1前列癌细胞中的表达及对凋亡的影响:通过半定量RT-PCR、细胞免疫荧光以及Westernblotting,在mRNA和蛋白水平检测到CRFR1和CRFR2均表达于RM-1细胞中;在CRF介导的促凋亡作用中,它能通过下调Bcl-2(抗凋亡基因)及上调Bax(促凋亡基因)的蛋白表达从而增强线粒体膜电位超级化,最终激活caspases-9。与之相反,UCN2能上调Bcl-2,下调Bax的蛋白表达,最终抑制凋亡。以上两种受体对于凋亡发挥的相反的作用均可被相应的拮抗剂所阻断。同时,在UCN2对CRFR2的作用中,Akt和CREB在短时间内先后被激活且呈时间依赖性,且预先给予LY29004(PI3K抑制剂)处理后,CREB磷酸化被显著抑制,Bcl-2蛋白表达降低,此结果表明Akt和CREB可能参与了CRFR2介导的小鼠RM-1前列癌细胞抗凋亡作用。
综上所述,本文工作首次发现CRF两种亚型的受体表达于小鼠RM-1前列癌细胞中,且对凋亡具有相反的作用。这些CRF相关肽对前列腺癌细胞凋亡的影响能够帮助我们了解更多关于CRF系统在前列腺癌的作用,以及提供了一个潜在的治疗前列腺癌的靶点。
Corticotropin-releasing factor (CRF) related peptides and their receptors aredistributed in central nervous system (CNS) and periphery, which display quitedifferent pharmacological profiles. In CNS, CRF related peptides and their receptorsare critical in regulating behavioral response, mood activity, food intake, drugaddiction and so on. In periphery, CRF related peptides and their receptors playimportant roles in cardiovascular system, inflammatory response, metabolism,cancer and so on.
The distinct roles of CRF related peptides depend on the quantity and types ofthe ligands, which are also related to diverse subtypes and distributions of receptors.Both CRF related peptides and their receptors have been detected in the striatum ofthe CNS and prostate cancer tissues, however, the detailed effects of CRF receptorson cocaine addiction in corticostriatal circuit and the apoptosis of prostate cancercells are far from clear. Based on the present observation in CNS, CRF familypeptides enhanced corticostriatal LTP under cocaine withdrawal condition, whichmay contribute to stress-induced relapse of cocaine abuse. Importantly, CRFreceptors mediated subtype-specific functional changes. CRFR1 appeared toenhance corticostriatal LTP under both physiological and cocaine withdrawalcondition, whereas CRFR2 was involved in modulating neuroadaptive changes onlyduring cocaine withdrawal. In periphery, CRF induced apoptosis via CRFR1 inRM-1 murine prostate cancer cells, which was associated with the upregulation of Bax and downregulation of Bcl-2. On the contrary, UCN2 repressed apoptosis viaCRFR2 in RM-1 cells, which was accompanied with phosphorylation of Akt andCREB, downregulation of Bax and upregulation of Bcl-2 .
In summary, we investigated the roles and relevant mechanisms of CRF relatedpeptides and their receptors in rats corticostriatal synaptic plasticity under cocainewithdrawal condition and in apoptosis of RM-1 murine prostate cancer cells, aimedto elaborate the different roles of CRF receptors in CNS and periphery.
Part 1 Roles of CRF receptors in long-term potentiation in ratcorticostriatal synapses under cocaine withdrawal
Similar to other abused drugs, main characteristics of cocaine addiction arecompulsive drug use and high rates of relapse during periods of abstinence. In the last15 years, a large number of studies were conducted to study the effects ofhypothalamic and extrahypothalamic CRF systems on cocaine abuse. Cocaineaddiction mechanisms may be similar to those that underlie learning and memoryprocesses which require the participation of corticostriatal circuit. Corticostriatalcircuit has been widely accepted as a brain center to form habits and storage. Thus far,the underlying roles of CRF related peptides and receptors in corticostriatal synapticplasticity during cocaine withdrawal are not well illustrated, yet. Long termpotentiation (LTP) has been regarded as an important cellular model of synapticplasticity. In the first part, the roles of two subtypes of CRFRs in rat corticostriatalsynaptic plasticity during cocaine withdrawal were investigated. Based on theobservations, cocaine withdrawal did not affect the basic electrophysiological properties of striatal neurons or the LTP in rats corticostriatal slices. Importantly, itwas found for the first time that CRF dose-dependently enhanced rats corticostriatalLTP in both the cocaine-withdrawal group and the saline group, which maycontribute to stress-induced relapse of cocaine abuse. In addition, the enhanced LTPwas reduced by pretreatment with either the CRFR1 selective antagonist (NBI 27914)or the CRFR2 selective antagonist (astression2B) in the cocaine withdrawal group.However, in the saline group, enhanced LTP was significantly attenuated only by theCRFR1 selective antagonist (NBI 27914). Futhermore, UCN2, the CRFR2 selectiveagonist, only potentiated corticostriatal LTP in the cocaine withdrawal group,meanwhile, that effect of UCN2 could be completely blocked by pretreatment withastression2B. Taken together, CRFR1 enhanced rats corticostriatal LTP under bothphysiological and cocaine withdrawal condition, but CRFR2 mediated that fuctiononly under cocaine withdrawal condition.
In conclusion, CRF family peptides enhanced rats corticostriatal LTP undercocaine withdrawal condition. Importantly, CRF receptors mediated subtype-specificfunction. CRFR1 appeared to enhance corticostriatal LTP under both physiologicaland cocaine withdrawal condition, whereas CRFR2 was involved in modulatingneuroadaptive changes only under cocaine withdrawal condition. Therefore, thestate-dependent changes of CRFR2 function might be an important mechanism thatcontributes to cocaine relapse, which might be an attractive novel target for thetreatment of relapse during cocaine withdrawal.
Part 2 Different roles of CRF receptors in apoptosis of RM-1murine prostate cancer cells
Roles of CRF related peptides and their receptors in periphery, especially incancer cells have become confusing recently. It is reported that UCN has beendetected in human prostate tumor specimens. But till now, there was no studyexploring CRFRs’expression in prostate tumor cells and the correspondingphysiological and pathological effects. In the second part, the expressions andpotential mechanisms of CRFRs’effects on apoptosis in RM-1 cells wereinvestigated for the first time. Here, the expressions of CRFR1 and CRFR2 at bothmRNA and protein levels in RM-1 were detected using semi-quantitative RT-PCR,immunofluorescence and Western blotting analysis. CRF treatment was accompaniedwith Bcl-2 (anti-apoptotic gene) downregulation, Bax (pro-apoptotic gene)upregulation, hyperpolarization of the mitochondrial membrane potential andactivation of caspase-9. On the contrary, the inhibited apoptosis by UCN2 wasassociated with upregulating Bcl-2 and downregulating Bax expressions. All effectsof CRF/UCN2 were abolished by antarlamin/antisauvagine-30, selective CRFR1 andCRFR2 antagonist, respectively. Meanwhile, UCN2 repressed apoptosis via CRFR2,which was accompanied with time-dependent phosphorylation of Akt andsubsequently phosphorylation of CREB in a short time. LY29004, a PI3K inhibitor,significantly inhibited both CREB phosphorylation and subsequent Bcl-2 expressiontriggered by UCN2, which suggested that Akt&CREB may be involved inanti-apoptosis in RM-1 murine prostate cancer cells mediated by CRFR2.
In summary, the present study first demonstrated the expression of two subtypesof CRFRs, which had opposite apoptotic effects in RM-1 murine prostate cancer cells.These findings accumulated theoretical evidences for illuminating the roles of CRFsystem in prostate tumor cells, especially provided a potential target for the treatmentof prostate tumor.
在中枢的皮质纹状体及外周的前列腺癌组织中均有大量的CRF相关肽及其受体的表达,但其对可卡因戒断情况下皮质纹状体通路突触可塑性和前列腺癌细胞凋亡的作用尚未完全明了。本文研究发现:在中枢系统中,CRF能增强可卡因戒断情况下大鼠皮质纹状体神经通路LTP,且不同亚型受体具有不同作用:CRF激活CRFR1均能增强生理和可卡因戒断病理情况下大鼠皮质纹状体神经通路LTP,而激活CRFR2只增强可卡因戒断大鼠的皮质纹状体神经通路LTP。在外周,CRF通过CRFR1,调节Bax/Bcl-2比例从而促进小鼠RM-1前列癌细胞凋亡。同时,UCN2却通过CRFR2磷酸化Akt和CREB,上调Bcl-2,下调Bax表达,最终抑制RM-1细胞凋亡。
综上所述,本实验首次研究CRF相关肽及其受体对可卡因戒断大鼠的皮质纹状体神经通路LTP及对小鼠RM-1前列腺癌细胞凋亡的作用及机制,从一个侧面初步阐述了CRF受体在中枢和外周的不同作用。
第一部分CRF相关肽及其受体对可卡因戒断大鼠的皮质纹状体神经通路LTP的影响
同其它成瘾药物类似,可卡因滥用主要表现为长期滥用和高复吸率。在最近15年中,许多的研究证实下丘脑及下丘脑外CRF系统能影响可卡因滥用。可卡因成瘾过程中可能涉及类似于学习和记忆的机制,而这种机制需要皮质纹状体通路的参与。同时,皮质纹状体通路已经被广泛认为是习惯形成和存储的大脑中心。LTP是研究突触可塑性的重要实验模型。本文工作初步探讨了在可卡因戒断情况下,CRF受体的两种亚型对大鼠皮质纹状体突触可塑性的影响。实验结显示无论在可卡因戒断组还是在生理盐水组,CRF均呈剂量依赖性地增强大鼠皮质纹状体神经通路LTP。这一结果表明CRF相关肽可能会通过增强皮质纹状体神经通路LTP来导致复吸。在可卡因戒断组中,预先给予CRFR1选择性拮抗剂(NBI27914)或者CRFR2选择性拮抗剂(astression2B),CRF诱导增强的LTP均能被逆转;然而在生理盐水组中,CRF诱导增强的LTP只能被astression2B减弱。值得注意的是,外源性给予UCN2(CRFR2选择性激动剂)可以显著性增强可卡因戒断大鼠的皮质纹状体神经通路LTP,而对生理盐水组脑片的LTP没有影响;UCN2的LTP增强作用被astression2B完全阻断。综合本研究的实验结果,CRFR1在生理条件和可卡因戒断情况下均表达并发挥了增强大鼠皮质纹状体神经通路LTP,然而CRFR2只有在可卡因戒断情况下才发挥此作用。
综上所述,在可卡因戒断情况下,CRF相关肽能增加皮质纹状体神经通路LTP,而这一改变能促进应激导致的可卡因复吸。更重要的是,不同的CRF受体介导了不同的功能,其中CRFR1在生理和可卡因戒断病理情况下都能增强皮质纹状体神经通路LTP,而CRFR2只在可卡因戒断情况下参与调节神经适应性变化。这些研究结果提示CRFR2的功能在可卡因戒断后发生了明显改变,这种特异性变化可能是可卡因复吸的一个重要机制,有可能成为新的药物作用靶点来影响可卡因戒断后的复吸。
第二部分不同CRF受体对小鼠RM-1前列癌细胞凋亡的影响
CRF相关肽及其受体在外周的作用特别是对肿瘤的影响成为当前的研究热点。2002年,几位美国学者在人类前列腺癌标本中首次发现了UCN,然而有关CRFR的表达及其在前列腺癌细胞中的具体生理病理作用尚未报导。本文第二部分主要探讨了CRFRs在小鼠RM-1前列癌细胞中的表达及对凋亡的影响:通过半定量RT-PCR、细胞免疫荧光以及Westernblotting,在mRNA和蛋白水平检测到CRFR1和CRFR2均表达于RM-1细胞中;在CRF介导的促凋亡作用中,它能通过下调Bcl-2(抗凋亡基因)及上调Bax(促凋亡基因)的蛋白表达从而增强线粒体膜电位超级化,最终激活caspases-9。与之相反,UCN2能上调Bcl-2,下调Bax的蛋白表达,最终抑制凋亡。以上两种受体对于凋亡发挥的相反的作用均可被相应的拮抗剂所阻断。同时,在UCN2对CRFR2的作用中,Akt和CREB在短时间内先后被激活且呈时间依赖性,且预先给予LY29004(PI3K抑制剂)处理后,CREB磷酸化被显著抑制,Bcl-2蛋白表达降低,此结果表明Akt和CREB可能参与了CRFR2介导的小鼠RM-1前列癌细胞抗凋亡作用。
综上所述,本文工作首次发现CRF两种亚型的受体表达于小鼠RM-1前列癌细胞中,且对凋亡具有相反的作用。这些CRF相关肽对前列腺癌细胞凋亡的影响能够帮助我们了解更多关于CRF系统在前列腺癌的作用,以及提供了一个潜在的治疗前列腺癌的靶点。
Corticotropin-releasing factor (CRF) related peptides and their receptors aredistributed in central nervous system (CNS) and periphery, which display quitedifferent pharmacological profiles. In CNS, CRF related peptides and their receptorsare critical in regulating behavioral response, mood activity, food intake, drugaddiction and so on. In periphery, CRF related peptides and their receptors playimportant roles in cardiovascular system, inflammatory response, metabolism,cancer and so on.
The distinct roles of CRF related peptides depend on the quantity and types ofthe ligands, which are also related to diverse subtypes and distributions of receptors.Both CRF related peptides and their receptors have been detected in the striatum ofthe CNS and prostate cancer tissues, however, the detailed effects of CRF receptorson cocaine addiction in corticostriatal circuit and the apoptosis of prostate cancercells are far from clear. Based on the present observation in CNS, CRF familypeptides enhanced corticostriatal LTP under cocaine withdrawal condition, whichmay contribute to stress-induced relapse of cocaine abuse. Importantly, CRFreceptors mediated subtype-specific functional changes. CRFR1 appeared toenhance corticostriatal LTP under both physiological and cocaine withdrawalcondition, whereas CRFR2 was involved in modulating neuroadaptive changes onlyduring cocaine withdrawal. In periphery, CRF induced apoptosis via CRFR1 inRM-1 murine prostate cancer cells, which was associated with the upregulation of Bax and downregulation of Bcl-2. On the contrary, UCN2 repressed apoptosis viaCRFR2 in RM-1 cells, which was accompanied with phosphorylation of Akt andCREB, downregulation of Bax and upregulation of Bcl-2 .
In summary, we investigated the roles and relevant mechanisms of CRF relatedpeptides and their receptors in rats corticostriatal synaptic plasticity under cocainewithdrawal condition and in apoptosis of RM-1 murine prostate cancer cells, aimedto elaborate the different roles of CRF receptors in CNS and periphery.
Part 1 Roles of CRF receptors in long-term potentiation in ratcorticostriatal synapses under cocaine withdrawal
Similar to other abused drugs, main characteristics of cocaine addiction arecompulsive drug use and high rates of relapse during periods of abstinence. In the last15 years, a large number of studies were conducted to study the effects ofhypothalamic and extrahypothalamic CRF systems on cocaine abuse. Cocaineaddiction mechanisms may be similar to those that underlie learning and memoryprocesses which require the participation of corticostriatal circuit. Corticostriatalcircuit has been widely accepted as a brain center to form habits and storage. Thus far,the underlying roles of CRF related peptides and receptors in corticostriatal synapticplasticity during cocaine withdrawal are not well illustrated, yet. Long termpotentiation (LTP) has been regarded as an important cellular model of synapticplasticity. In the first part, the roles of two subtypes of CRFRs in rat corticostriatalsynaptic plasticity during cocaine withdrawal were investigated. Based on theobservations, cocaine withdrawal did not affect the basic electrophysiological properties of striatal neurons or the LTP in rats corticostriatal slices. Importantly, itwas found for the first time that CRF dose-dependently enhanced rats corticostriatalLTP in both the cocaine-withdrawal group and the saline group, which maycontribute to stress-induced relapse of cocaine abuse. In addition, the enhanced LTPwas reduced by pretreatment with either the CRFR1 selective antagonist (NBI 27914)or the CRFR2 selective antagonist (astression2B) in the cocaine withdrawal group.However, in the saline group, enhanced LTP was significantly attenuated only by theCRFR1 selective antagonist (NBI 27914). Futhermore, UCN2, the CRFR2 selectiveagonist, only potentiated corticostriatal LTP in the cocaine withdrawal group,meanwhile, that effect of UCN2 could be completely blocked by pretreatment withastression2B. Taken together, CRFR1 enhanced rats corticostriatal LTP under bothphysiological and cocaine withdrawal condition, but CRFR2 mediated that fuctiononly under cocaine withdrawal condition.
In conclusion, CRF family peptides enhanced rats corticostriatal LTP undercocaine withdrawal condition. Importantly, CRF receptors mediated subtype-specificfunction. CRFR1 appeared to enhance corticostriatal LTP under both physiologicaland cocaine withdrawal condition, whereas CRFR2 was involved in modulatingneuroadaptive changes only under cocaine withdrawal condition. Therefore, thestate-dependent changes of CRFR2 function might be an important mechanism thatcontributes to cocaine relapse, which might be an attractive novel target for thetreatment of relapse during cocaine withdrawal.
Part 2 Different roles of CRF receptors in apoptosis of RM-1murine prostate cancer cells
Roles of CRF related peptides and their receptors in periphery, especially incancer cells have become confusing recently. It is reported that UCN has beendetected in human prostate tumor specimens. But till now, there was no studyexploring CRFRs’expression in prostate tumor cells and the correspondingphysiological and pathological effects. In the second part, the expressions andpotential mechanisms of CRFRs’effects on apoptosis in RM-1 cells wereinvestigated for the first time. Here, the expressions of CRFR1 and CRFR2 at bothmRNA and protein levels in RM-1 were detected using semi-quantitative RT-PCR,immunofluorescence and Western blotting analysis. CRF treatment was accompaniedwith Bcl-2 (anti-apoptotic gene) downregulation, Bax (pro-apoptotic gene)upregulation, hyperpolarization of the mitochondrial membrane potential andactivation of caspase-9. On the contrary, the inhibited apoptosis by UCN2 wasassociated with upregulating Bcl-2 and downregulating Bax expressions. All effectsof CRF/UCN2 were abolished by antarlamin/antisauvagine-30, selective CRFR1 andCRFR2 antagonist, respectively. Meanwhile, UCN2 repressed apoptosis via CRFR2,which was accompanied with time-dependent phosphorylation of Akt andsubsequently phosphorylation of CREB in a short time. LY29004, a PI3K inhibitor,significantly inhibited both CREB phosphorylation and subsequent Bcl-2 expressiontriggered by UCN2, which suggested that Akt&CREB may be involved inanti-apoptosis in RM-1 murine prostate cancer cells mediated by CRFR2.
In summary, the present study first demonstrated the expression of two subtypesof CRFRs, which had opposite apoptotic effects in RM-1 murine prostate cancer cells.These findings accumulated theoretical evidences for illuminating the roles of CRFsystem in prostate tumor cells, especially provided a potential target for the treatmentof prostate tumor.
引文
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