前列腺癌非激素依赖转化中磷酸化蛋白差异及其作用途径研究
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摘要
一、研究背景
前列腺癌(prostate cancer, CaP)是一种老年男性常见病,其发病率在美国居男性恶性肿瘤之首,占男性死亡原因的第二位。自1941年Huggins等采用雄激素剥夺疗法治疗晚期前列腺癌取得显著疗效后,激素治疗逐渐成为治疗前列腺癌的一项重要的方法。内分泌治疗对大多数CaP有明显的疗效但有其局限性,一般仅能维持6～18个月,几乎所有CaP患者最终均转为雄激素非依赖前列腺癌(androgen- independent prostate cancer, AIPC),进而发展为激素难治性前列腺癌(hormone refractory prostate cancer, HRPC)。目前对HRPC缺乏有效的治疗方法,放疗、化疗、生物治疗等均不能有效地控制肿瘤进展,其平均生存期为9～18个月。目前临床对激素非依赖前列腺癌发病机制主要集中在细胞的克隆学说、肿瘤基因的激活或融合、抑癌基因的失活、抗凋亡基因的上调、雄激素的共刺激因子激活、雄激素受体的突变或超敏和前列腺组织雄激素合成等多个方面。虽然有关CaP雄激素依赖进展的研究及学说很多,但雄激素非依赖的发生机制至今尚不完全清楚。翻译后的蛋白质修饰在生物体的功能上起关键作用,而可逆的磷酸化几乎调节着细胞信号传导、细胞分化、细胞生长、细胞凋亡等几乎所有的生命活动。在前列腺癌内分泌治疗过程中非激素依赖转化过程成中,蛋白质的磷酸化也发挥重要的作用。
二、研究目的
利用蛋白组学技术和生物信息学研究激素依赖前列腺癌细胞转化为激素非依赖前列腺癌细胞过程中差异磷酸化蛋白的表达,从整体水平探索磷酸化蛋白质的作用模式、功能调节以及蛋白质群内相互作用,揭示可能介导转化过程的信号通路,有助于为更全面的了解前列腺癌非激素依赖转化的机制,为其治疗提供新的治疗靶点。
三、实验方法
(一)、培养人激素依赖性前列腺癌细胞株(LNCaP),并通过除去培养基中的雄激素诱导建立起激素非依赖性前列腺癌细胞株(LNCaP-AI),通过CCK-8法验证LNCaP-AI在去雄环境下的增值能力以及测定在不同雄激素浓度下分泌PSA的情况。
(二)、分别提取LNCaP细胞和LNCaP-AI的总蛋白,采用固定金属螯合亲和层析(immobilized metal affinity chromatography, IMAC)富集两种细胞的磷酸化蛋白,并分离纯化,利用二维凝胶电泳技术分离两种细胞磷酸化蛋白质组样品,获得满意的两种细胞株的磷酸化蛋白双向凝胶电泳图谱,凝胶经银染显色后,PSQuest分析软件进行比较分析,筛选出差异3倍以上的且超过半数胶中均存在的蛋白点。将差异点从胶中切出,进行胶内酶解,得到肽段混合物。应用基质辅助的激光解吸飞行时间质谱(MALDI-TOF-MS)与串联质谱(MS/MS)方法对差异点进行磷酸化蛋白质鉴定。使用Mascot查询软件搜索SWISS-PROT以及NCBInr数据库做生物信息学分析。
(三)、从2-DE筛选出的差异磷酸化蛋白中挑选了Peroxiredoxin-2和HSP27两种蛋白,应用western blot的方法进行验证。
(四)、运用STRING数据库和软件对LNCaP-AI中所有的、上调的、下调的鉴定的磷酸化蛋白质进行一级相互作用预测,探讨其在信号通路中的作用。
四、结果
(一)、LNCaP前列腺癌细胞在去激素的环境下生长迅速受到抑制,一周左右开始处于自分泌状态,1个月后逐渐适应了去雄激素的环境,6个月后能够正常增殖和传代,成为激素非依赖的LNCaP-AI细胞亚系,其PSA分泌水平随雄激素水平的增高而增加,但表达PSA的水平要低于LNCaP细胞。
(二)、采用磷酸化富集及二维凝胶电泳分离LNCaP细胞和LNCaP-AI细胞磷酸化蛋白质组样品,凝胶经银染显色后,PDQuest 7.1.0软件进行比较分析。共发现28个点差异在3倍以上,其中有13个点在LNCaP-AI细胞组表达上调,15个点在LNCaP细胞对照组表达上调。
(三)、应用MALDI-TOF-MS质谱技术(Voyager-DE STR质谱仪,美国Applied Biosystems公司)对差异蛋白质点进行鉴定,用Mascot数据库。共鉴定出包括核磷蛋白(Nucleophosmin)、热休克蛋白β1(Heat shock protein beta-1, HSP27)、过氧化物还原酶2和6(Peroxiredoxin-2和Peroxiredoxin-6)等参与信号转导、细胞骨架调节、能量代谢等有关的17种蛋白质。
(四)、应用Western-blot的方法对包括Peroxiredoxin-2 ,Heat shock protein beta-1在内的2种蛋白进行了验证,蛋白变化趋势与质谱鉴定结果一致。
(五)、应用STRING数据库和文献支持分析,认为P53与HSP27的相互作用及MAPK信号通路、抗氧化蛋白活性的减低在激素非依赖前列腺癌转化过程中发挥重要作用,因此阻断MAPK信号通路或提高过氧化物还原酶活性可以提供一种新的治疗前列腺癌方法。
五、结论
LNCaP-AI细胞系是从LNCaP细胞系经过去雄激素干预后建立的细胞亚系,可以模拟临床上内分泌治疗过程中,前列腺癌由激素依赖发展为雄激素非依赖的过程,并且两者细胞具有同源性,两者有可比性,可以用来观察前列腺癌由激素依赖向非依赖转变过程的分子生物学变化。通过磷酸化蛋白富集策略,比较蛋白质组学和生物信息学,成功鉴定了包括信号转导蛋白、细胞骨架蛋白、能量代谢相关蛋白等17种在激素非依赖前列腺癌中差异表达的磷酸化蛋白。生物信息学分析认为P53与HSP27的相互作用及MAPK信号通路、抗氧化蛋白活性的减低在激素非依赖前列腺癌转化过程中发挥重要作用,因此阻断MAPK信号通路和提高过氧化物还原酶活性可提供一种新的治疗前列腺癌方法。
Background
Prostate cancer(CaP)is a common disease in aged men. In America, CaP is the most common malignant illness in men, and the second leading cause of cancer death. The effect on prostate cancer of lowering circulating androgens by castration or by reducing plasma testosterone levels through interference with the estrogen-driven diencephalic pituitary feedback mechanism was first observed and described by Huggins in 1941. Patients who develop metastatic disease are often initially treated with hormone deprivation by medical castration or surgical castration. Most metastatic prostatic tumors can therefore be treated effectively by hormonal therapies. However, hormone ablation results in only a temporary regression of these tumors. Inevitably, some tumors in the population become androgen-independent prostate cancer(AICP) usually within 6–18 months, At present, Options following initial treatment include secondline hormonal therapy or systemic chemotherapy when metastatic disease develops. Chemotherapy had led to stabilization of disease and improvement of symptoms but did not increase survival in patients with AICP. The molecular mechanisms by which prostate cancer cells become androgen independent are unknown and remain the focus of intensive research. Several factors have been demonstrated to be involved in the development of androgen-independent growth in prostate cancer. For instance, preexisting genetic changes in prostate cancer stem cells, oncogenes, the inhibition of apoptosis, ligand-independent AR activation, AR hypersensitivity, change of AR specificity (AR mutations), gene fusions and Androgen synthesis in AIPC tissues have been observed in androgen-independent prostate cancer. The molecular Pathogenesis of androgen-independent prostate cancer is so complicated that the mechanism of this disease remain uncertain. Reversible Phosphorylation of proteins play s a key role in many cellular Processes including signal transduction, proliferation apoptosis, differentiation, cytoskeletal regulation and so on. It plays an important role in the pathogenesis of prostate cancer to the androgen-independent state.
Objective
By the way of proteomics and bioinformatics, we can known about global differential phosphoproteins in androgen-independent prostate and reveal the rule of the phosphoproteins, the function and interactions of as many proteins as possible at the global level. It is useful for us to elucidate the molecular mechanisms underlying the formation of AICP and to identify new molecular targets that can be used to develop treatments for the disease.
Materials and methods
1. We generated an androgen-independent LNCaP-AI prostatic carcinoma cell line from androgen-dependent LNCaP cells by in vitro cell culture medium with 10% fetal bovine serum(FBS) depleted of steroids by charcoal/dextan-treatment(CDS medium. Tumor cell growth was estimated by the CCK-8 assay, PSA protein was measured in cell culture supernatants from the LNCaP and LNCaP-AI cells with medium containing different concentrations of androgen.
2. We extracted the total proteins of LNCaP and LNCaP-AI cell, then used immobilized metal affinity chromatography(IMAC) to enrich phosphoproteins from cell proteins. Proteins extracted from LNCaP and LNCaP-AI were separared by two-dimendional gel electophoresis(2-DE). Analytical gels were stained with silver nitate. The stained gels were analyzed with PDQuest software. The protein spots exhibiting statistically alternations between the two groups through computer image analysis. 3 fold differential protein spots were excised from preparative gels and digested into peptides and analyzed by MALDI-TOF-MS. Protein identification using peptide mass fingerprinting(PMF) was performed by the MASCOT search engine against the MSDB(Swissprot or NCBI) protein database.
3. Two differential phosphorylated proteins ,Peroxiredoxin-2 and HSP27, from all the identified proteins were chosen to be testified by western blot analysis to substantiate the 2-DE results.
4. By using String database and software to analysis the relationships between the up-regulated, down-regulated and all proteins in LNCaP-AI cells identified by proteomics respectively to discover the relationships and set the associations between the relationships and the biological process.
Result
1. Initially, the proliferation of LNCaP cells were suppressed rapidly in the absence of hormone and laid in autocrine status after about 1 week. 1 months later, the cells gradually adapted to the no hormone circumstance and 6 months later began to proliferate, at this time the cells become androgen independent LNCaP-AI cell line. LNCaP- AI showed to be androgen-independent and grows equally well with or without androgens. PSA level in LNCaP-AI cell culture supernatant increased parallelly with concentrations of androgen. The secretion of PSA is still responsive to androgens, but to a much lesser extent than in the original LNCaP.
2. Through the PDQuest software analyzed the stained gels, a total 28 protein spots had been detected in protein profile of LNCaP-AI and LNCaP cells, which exhibiting a consistent, more than threefold phosphrylation level. Among them, 13 exhibiting protein up-regulation and 15 exhibiting down-regulation in LNCaP-AI cells, compared with LNCaP cells.
3. Data were then searched with MASCOT, a total of 17 prosteins were identified, these differential phosphoproteins included cell signaling proteins, cytoskeletal proteins, energy metabolism regulators such as Nucleophosmin, Heat shock protein beta-1, Peroxiredoxin-2 , Peroxiredoxin-6, and so on.
4. The western blot data showed that total HSP27 protein was found significantly up-regulated in LNCaP-AI cell lines, while total Pereoxiredoxin-2 protein was found significantly down-regulated in LNCaP-AI cell lined. The extents of the changes of these two proteins in LNCaP-AI were similar to that observed in the 2-DE analysis.
5. Supported by the STRING database and document analysis, the interaction of P53 and HSP27 and furthermore the MAPK pathway which involved in may play an important role of leading the transition of androgen-dependent prostate cells into androgen-independent prostate cells. Decrease of the function of eliminating peroxides generated during metabolism may be another important mechanism leads to the transition of androgen-dependent prostate cancer into androgen-independent prostate cancer.
conclusion
LNCaP-AI cell was developed from LNCaP cell under the circumstance of androgen ablation. This kind of CaP cell model could imitate the process from androgen-dependent prostate cancer to androgen-independent prostate cancer during endocrine therapy of CaP. LNCaP-AI cell was homology with LNCaP cell and could be compared with it. The cell model is an ideal model to study the pathogenesis for revealing signaling pathways of importance for transition of androgen dependent prostate cancer into androgen independent prostate cancer. We successfully identified 17 differential phosphoproteins including cell signaling proteins, cytoskeletal proteins, and energy metabolism regulators by IMPC strategy of phosphoprotein enrichment, proteomics technology and bioinformatics technology. Bioinformatics analysis reveals the interaction of P53 and HSP27 and furthermore the MAPK pathway which involved in and the decrease of the function of eliminating peroxides generated during metabolism may play an important role of leading the transition of androgen-dependent prostate cells into androgen-independent prostate cells. Thus, block of the MAPK signaling pathway and enhance the function of eliminating peroxides may be helpful to androgen-independent prostate cancer.
前列腺癌(prostate cancer, CaP)是一种老年男性常见病,其发病率在美国居男性恶性肿瘤之首,占男性死亡原因的第二位。自1941年Huggins等采用雄激素剥夺疗法治疗晚期前列腺癌取得显著疗效后,激素治疗逐渐成为治疗前列腺癌的一项重要的方法。内分泌治疗对大多数CaP有明显的疗效但有其局限性,一般仅能维持6～18个月,几乎所有CaP患者最终均转为雄激素非依赖前列腺癌(androgen- independent prostate cancer, AIPC),进而发展为激素难治性前列腺癌(hormone refractory prostate cancer, HRPC)。目前对HRPC缺乏有效的治疗方法,放疗、化疗、生物治疗等均不能有效地控制肿瘤进展,其平均生存期为9～18个月。目前临床对激素非依赖前列腺癌发病机制主要集中在细胞的克隆学说、肿瘤基因的激活或融合、抑癌基因的失活、抗凋亡基因的上调、雄激素的共刺激因子激活、雄激素受体的突变或超敏和前列腺组织雄激素合成等多个方面。虽然有关CaP雄激素依赖进展的研究及学说很多,但雄激素非依赖的发生机制至今尚不完全清楚。翻译后的蛋白质修饰在生物体的功能上起关键作用,而可逆的磷酸化几乎调节着细胞信号传导、细胞分化、细胞生长、细胞凋亡等几乎所有的生命活动。在前列腺癌内分泌治疗过程中非激素依赖转化过程成中,蛋白质的磷酸化也发挥重要的作用。
二、研究目的
利用蛋白组学技术和生物信息学研究激素依赖前列腺癌细胞转化为激素非依赖前列腺癌细胞过程中差异磷酸化蛋白的表达,从整体水平探索磷酸化蛋白质的作用模式、功能调节以及蛋白质群内相互作用,揭示可能介导转化过程的信号通路,有助于为更全面的了解前列腺癌非激素依赖转化的机制,为其治疗提供新的治疗靶点。
三、实验方法
(一)、培养人激素依赖性前列腺癌细胞株(LNCaP),并通过除去培养基中的雄激素诱导建立起激素非依赖性前列腺癌细胞株(LNCaP-AI),通过CCK-8法验证LNCaP-AI在去雄环境下的增值能力以及测定在不同雄激素浓度下分泌PSA的情况。
(二)、分别提取LNCaP细胞和LNCaP-AI的总蛋白,采用固定金属螯合亲和层析(immobilized metal affinity chromatography, IMAC)富集两种细胞的磷酸化蛋白,并分离纯化,利用二维凝胶电泳技术分离两种细胞磷酸化蛋白质组样品,获得满意的两种细胞株的磷酸化蛋白双向凝胶电泳图谱,凝胶经银染显色后,PSQuest分析软件进行比较分析,筛选出差异3倍以上的且超过半数胶中均存在的蛋白点。将差异点从胶中切出,进行胶内酶解,得到肽段混合物。应用基质辅助的激光解吸飞行时间质谱(MALDI-TOF-MS)与串联质谱(MS/MS)方法对差异点进行磷酸化蛋白质鉴定。使用Mascot查询软件搜索SWISS-PROT以及NCBInr数据库做生物信息学分析。
(三)、从2-DE筛选出的差异磷酸化蛋白中挑选了Peroxiredoxin-2和HSP27两种蛋白,应用western blot的方法进行验证。
(四)、运用STRING数据库和软件对LNCaP-AI中所有的、上调的、下调的鉴定的磷酸化蛋白质进行一级相互作用预测,探讨其在信号通路中的作用。
四、结果
(一)、LNCaP前列腺癌细胞在去激素的环境下生长迅速受到抑制,一周左右开始处于自分泌状态,1个月后逐渐适应了去雄激素的环境,6个月后能够正常增殖和传代,成为激素非依赖的LNCaP-AI细胞亚系,其PSA分泌水平随雄激素水平的增高而增加,但表达PSA的水平要低于LNCaP细胞。
(二)、采用磷酸化富集及二维凝胶电泳分离LNCaP细胞和LNCaP-AI细胞磷酸化蛋白质组样品,凝胶经银染显色后,PDQuest 7.1.0软件进行比较分析。共发现28个点差异在3倍以上,其中有13个点在LNCaP-AI细胞组表达上调,15个点在LNCaP细胞对照组表达上调。
(三)、应用MALDI-TOF-MS质谱技术(Voyager-DE STR质谱仪,美国Applied Biosystems公司)对差异蛋白质点进行鉴定,用Mascot数据库。共鉴定出包括核磷蛋白(Nucleophosmin)、热休克蛋白β1(Heat shock protein beta-1, HSP27)、过氧化物还原酶2和6(Peroxiredoxin-2和Peroxiredoxin-6)等参与信号转导、细胞骨架调节、能量代谢等有关的17种蛋白质。
(四)、应用Western-blot的方法对包括Peroxiredoxin-2 ,Heat shock protein beta-1在内的2种蛋白进行了验证,蛋白变化趋势与质谱鉴定结果一致。
(五)、应用STRING数据库和文献支持分析,认为P53与HSP27的相互作用及MAPK信号通路、抗氧化蛋白活性的减低在激素非依赖前列腺癌转化过程中发挥重要作用,因此阻断MAPK信号通路或提高过氧化物还原酶活性可以提供一种新的治疗前列腺癌方法。
五、结论
LNCaP-AI细胞系是从LNCaP细胞系经过去雄激素干预后建立的细胞亚系,可以模拟临床上内分泌治疗过程中,前列腺癌由激素依赖发展为雄激素非依赖的过程,并且两者细胞具有同源性,两者有可比性,可以用来观察前列腺癌由激素依赖向非依赖转变过程的分子生物学变化。通过磷酸化蛋白富集策略,比较蛋白质组学和生物信息学,成功鉴定了包括信号转导蛋白、细胞骨架蛋白、能量代谢相关蛋白等17种在激素非依赖前列腺癌中差异表达的磷酸化蛋白。生物信息学分析认为P53与HSP27的相互作用及MAPK信号通路、抗氧化蛋白活性的减低在激素非依赖前列腺癌转化过程中发挥重要作用,因此阻断MAPK信号通路和提高过氧化物还原酶活性可提供一种新的治疗前列腺癌方法。
Background
Prostate cancer(CaP)is a common disease in aged men. In America, CaP is the most common malignant illness in men, and the second leading cause of cancer death. The effect on prostate cancer of lowering circulating androgens by castration or by reducing plasma testosterone levels through interference with the estrogen-driven diencephalic pituitary feedback mechanism was first observed and described by Huggins in 1941. Patients who develop metastatic disease are often initially treated with hormone deprivation by medical castration or surgical castration. Most metastatic prostatic tumors can therefore be treated effectively by hormonal therapies. However, hormone ablation results in only a temporary regression of these tumors. Inevitably, some tumors in the population become androgen-independent prostate cancer(AICP) usually within 6–18 months, At present, Options following initial treatment include secondline hormonal therapy or systemic chemotherapy when metastatic disease develops. Chemotherapy had led to stabilization of disease and improvement of symptoms but did not increase survival in patients with AICP. The molecular mechanisms by which prostate cancer cells become androgen independent are unknown and remain the focus of intensive research. Several factors have been demonstrated to be involved in the development of androgen-independent growth in prostate cancer. For instance, preexisting genetic changes in prostate cancer stem cells, oncogenes, the inhibition of apoptosis, ligand-independent AR activation, AR hypersensitivity, change of AR specificity (AR mutations), gene fusions and Androgen synthesis in AIPC tissues have been observed in androgen-independent prostate cancer. The molecular Pathogenesis of androgen-independent prostate cancer is so complicated that the mechanism of this disease remain uncertain. Reversible Phosphorylation of proteins play s a key role in many cellular Processes including signal transduction, proliferation apoptosis, differentiation, cytoskeletal regulation and so on. It plays an important role in the pathogenesis of prostate cancer to the androgen-independent state.
Objective
By the way of proteomics and bioinformatics, we can known about global differential phosphoproteins in androgen-independent prostate and reveal the rule of the phosphoproteins, the function and interactions of as many proteins as possible at the global level. It is useful for us to elucidate the molecular mechanisms underlying the formation of AICP and to identify new molecular targets that can be used to develop treatments for the disease.
Materials and methods
1. We generated an androgen-independent LNCaP-AI prostatic carcinoma cell line from androgen-dependent LNCaP cells by in vitro cell culture medium with 10% fetal bovine serum(FBS) depleted of steroids by charcoal/dextan-treatment(CDS medium. Tumor cell growth was estimated by the CCK-8 assay, PSA protein was measured in cell culture supernatants from the LNCaP and LNCaP-AI cells with medium containing different concentrations of androgen.
2. We extracted the total proteins of LNCaP and LNCaP-AI cell, then used immobilized metal affinity chromatography(IMAC) to enrich phosphoproteins from cell proteins. Proteins extracted from LNCaP and LNCaP-AI were separared by two-dimendional gel electophoresis(2-DE). Analytical gels were stained with silver nitate. The stained gels were analyzed with PDQuest software. The protein spots exhibiting statistically alternations between the two groups through computer image analysis. 3 fold differential protein spots were excised from preparative gels and digested into peptides and analyzed by MALDI-TOF-MS. Protein identification using peptide mass fingerprinting(PMF) was performed by the MASCOT search engine against the MSDB(Swissprot or NCBI) protein database.
3. Two differential phosphorylated proteins ,Peroxiredoxin-2 and HSP27, from all the identified proteins were chosen to be testified by western blot analysis to substantiate the 2-DE results.
4. By using String database and software to analysis the relationships between the up-regulated, down-regulated and all proteins in LNCaP-AI cells identified by proteomics respectively to discover the relationships and set the associations between the relationships and the biological process.
Result
1. Initially, the proliferation of LNCaP cells were suppressed rapidly in the absence of hormone and laid in autocrine status after about 1 week. 1 months later, the cells gradually adapted to the no hormone circumstance and 6 months later began to proliferate, at this time the cells become androgen independent LNCaP-AI cell line. LNCaP- AI showed to be androgen-independent and grows equally well with or without androgens. PSA level in LNCaP-AI cell culture supernatant increased parallelly with concentrations of androgen. The secretion of PSA is still responsive to androgens, but to a much lesser extent than in the original LNCaP.
2. Through the PDQuest software analyzed the stained gels, a total 28 protein spots had been detected in protein profile of LNCaP-AI and LNCaP cells, which exhibiting a consistent, more than threefold phosphrylation level. Among them, 13 exhibiting protein up-regulation and 15 exhibiting down-regulation in LNCaP-AI cells, compared with LNCaP cells.
3. Data were then searched with MASCOT, a total of 17 prosteins were identified, these differential phosphoproteins included cell signaling proteins, cytoskeletal proteins, energy metabolism regulators such as Nucleophosmin, Heat shock protein beta-1, Peroxiredoxin-2 , Peroxiredoxin-6, and so on.
4. The western blot data showed that total HSP27 protein was found significantly up-regulated in LNCaP-AI cell lines, while total Pereoxiredoxin-2 protein was found significantly down-regulated in LNCaP-AI cell lined. The extents of the changes of these two proteins in LNCaP-AI were similar to that observed in the 2-DE analysis.
5. Supported by the STRING database and document analysis, the interaction of P53 and HSP27 and furthermore the MAPK pathway which involved in may play an important role of leading the transition of androgen-dependent prostate cells into androgen-independent prostate cells. Decrease of the function of eliminating peroxides generated during metabolism may be another important mechanism leads to the transition of androgen-dependent prostate cancer into androgen-independent prostate cancer.
conclusion
LNCaP-AI cell was developed from LNCaP cell under the circumstance of androgen ablation. This kind of CaP cell model could imitate the process from androgen-dependent prostate cancer to androgen-independent prostate cancer during endocrine therapy of CaP. LNCaP-AI cell was homology with LNCaP cell and could be compared with it. The cell model is an ideal model to study the pathogenesis for revealing signaling pathways of importance for transition of androgen dependent prostate cancer into androgen independent prostate cancer. We successfully identified 17 differential phosphoproteins including cell signaling proteins, cytoskeletal proteins, and energy metabolism regulators by IMPC strategy of phosphoprotein enrichment, proteomics technology and bioinformatics technology. Bioinformatics analysis reveals the interaction of P53 and HSP27 and furthermore the MAPK pathway which involved in and the decrease of the function of eliminating peroxides generated during metabolism may play an important role of leading the transition of androgen-dependent prostate cells into androgen-independent prostate cells. Thus, block of the MAPK signaling pathway and enhance the function of eliminating peroxides may be helpful to androgen-independent prostate cancer.
引文
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