PTEN信号转导通路与肿瘤的多药耐药

基因调控、信号转导通路异常均可引起细胞增殖失控,导致肿瘤发生.肿瘤细胞对化疗药物耐药是肿瘤患者死亡的主要原因.细胞内药物有效浓度的降低、DNA损伤的修复障碍、基因的突变及异常表达、信号转导通路的异常等均参与了肿瘤细胞的多药耐药.张力蛋白同源10号染色体缺失的磷酸酶基因(phosphatase and tension homology deleted on chromosome ten gene,PTEN)是具有磷酸酶活性的抑癌基因,在多种肿瘤细胞中异常表达,主要通过抑制P13K/Akt/mTOR(mammalian target of rapamycin,mTOR)等多种信号转导通路参与细胞的增殖、凋亡及化疗耐药.因此,上调野生型PTEN的表达,或使用PBK/Akt/mTOR信号通路抑制剂,可逆转肿瘤细胞的多药耐药,提高传统化疗的疗效.     

PTEN与胃癌

胃癌的发生发展是一个多因素、多基因、多阶段、多途径有序的过程.人第10号染色体缺失的磷酸酶及张力蛋白同源的基因(PTEN)是迄今为止发现的第一个具有双重特异性磷酸酶活性的抑癌基因,调控着细胞周期和多种信号途径,在胃癌的发生发展中起重要作用.关于PTEN的进一步研究将为胃癌诊断、治疗及判断预后提供新的思路.     

PI3K/Akt信号通路在肿瘤化疗耐药中的作用

磷脂酰肌醇3-激酶-蛋白激酶B(PI3K/Akt)信号通路在细胞内发挥重要的作用,参与了许多生理和病理活动.目前研究发现在许多肿瘤中过度激活的PI3K/Akt信号通路与肿瘤化疗耐药的产生密切相关,体外研究显示采用PI3K/Akt信号通路抑制剂可以逆转肿瘤细胞的耐药.本文简要介绍了PI3K/Akt信号通路的基本组成结构,并重点介绍其在肿瘤化疗耐药中的作用.     

多药耐药相关蛋白基因与肿瘤耐药

多药耐药相关蛋白基因与肿瘤耐药徐萌综述李金瀚审校第一军医大学附属南方医院肿瘤科（广州市５１０５１５）多药耐药（ｍｕｌｔｉｄｒｕｇｒｅｓｉｓｔａｎｃｅ，ＭＤＲ）的产生是导致肿瘤产生耐药和化疗失败的原因之一。实验研究表明，ＭＤＲ包括三种表现形式：１）典型...     

PI3K/Akt/mTOR信号转导通路与非小细胞肺癌

肺癌是目前世界上发病率和死亡率最高的恶性肿瘤之一,其中非小细胞肺癌(non-small cell lung cancer,NSCLC)占肺癌的75%-85%,确诊时多属中晚期,常规放、化疗效果欠佳,5年生存率仅为5%-10%.PI3K/Akt/mTOR信号通路作为细胞内重要信号转导通路之一,通过影响下游多种效应分子的活化状态,与NSCLC的发生发展密切相关.本文综述了PI3K/Akt/mTOR信号通路的组成,其抑制凋亡、促进增殖的关键作用以及在NSCLC中的研究现状,以期为NSCLC的治疗寻找潜在的靶点.     

脑胶质瘤多药耐药与PI3K/Akt信号传导通路的关系及其治疗进展

胶质瘤细胞产生耐药性是导致肿瘤化疗失败的重要因素,其耐药机制尚未完全清楚。胶质瘤的恶性进展涉及多个信号转导通路的异常,其中P13K/Akt通路异常不仅与胶质瘤的发生、发展密切相关,而且在肿瘤的生长、对化疗药物的耐药性等方面都起着关键作用。本文着重对P13K/Akt通路与脑胶质瘤的关系及其化疗耐药的相关内容进行阐述。     

多药耐药基因与泌尿系肿瘤

多药耐药基因的异常表达是目前发现的癌症化疗失效的主要原因。ＭＤＲ１为有功能耐药基因，通过其编码产物Ｐ－糖蛋白发挥作用。本文综述了ＭＤＲ基因在泌尿系肿瘤中的研究近况。     

PTEN蛋白缺失与中国前列腺癌患者根治术后生化复发风险关系的研究

背景与目的：张力蛋白同源第10号染色体缺失的磷酸酶基因(phosphatase and tensin homolog deleted on chromosome 10,PTEN)缺失是西方国家前列腺癌中最常见的基因异常之一,与肿瘤的进展、预后均有一定相关性。鉴于前列腺癌的异质性,不同地区、人群间其基因表达谱存在广泛差异,本研究主要探讨PTEN蛋白缺失在中国前列腺癌患者中的发生率以及与生化复发的相关性。方法：选取2006—2011年225例局限性前列腺癌并采取根治切除术的患者为研究对象,回顾性收集所有患者的临床病理资料,包括确诊时年龄、血清前列腺特异性抗原(prostate-specific antigen,PSA)值、Gleason分级评分、TNM分期、手术切缘和术后生化复发与否及时间。将225例局限性前列腺癌根治切除标本的肿瘤组织及癌旁组织制成组织芯片(tissue microarray,TMA),采用免疫组织化学技术检测PTEN蛋白在肿瘤及癌旁组织中的表达。采用χ²检验分析前列腺癌组织中PTEN蛋白缺失与患者临床病理特征的相关性。运用Kaplan-Meier生存分析模型、Cox比例风险模型分析PTEN蛋白缺失及患者临床病理特征与生化复发的关系。结果：前列腺癌患者中PTEN蛋白缺失率为15%(33/217),且存在PTEN蛋白缺失的前列腺癌患者其确诊时血清PSA值(P=0.030)及年龄(P=0.009)要显著高于PTEN表达的前列腺癌患者。单因素生存分析显示,PTEN表达情况(P=0.013 1)、确诊时血清PSA值(P=0.000 4)和Gleason分级评分(P=0.019 8)与前列腺癌患者的生化复发相关。Cox多因素分析结果表明,PTEN蛋白表达情况(HR=0.536,P=0.044)、确诊时血清PSA值(HR=1.879,P=0.001)和Gleason分级评分(HR=1.361,P=0.030)为前列腺癌患者生化复发的独立预后因素。结论：PTEN蛋白表达情况是局限性前列腺癌患者根治术后生化复发的独立预后因素,检测PTEN蛋白有望改善根治术后前列腺癌患者的管理及指导进一步治疗。     

磷酸化Akt和PTEN在非小细胞肺癌组织中的表达及其相关性

目的:探讨磷酸化Akt(p-Akt)与PTEN表达在非小细胞肺癌(NSCLC)侵袭、转移中的作用及其相关关系。方法:应用免疫组织化学SP法检测20例正常肺组织和102例非小细胞肺癌癌组织中p-Akt和PTEN蛋白的表达。结果:正常肺组织p-Akt为阴性表达,而PTEN为阳性表达;非小细胞肺癌癌组织中p-Akt表达的阳性率为41.2%(42/102),PTEN失表达率为46.1%(47/102)。p-Akt阳性表达和PTEN的失表达与肿瘤组织分化程度、临床分期以及有无淋巴结和远处转移相关。p-Akt和PTEN表达呈显著负相关(Phi r=-0.425,P<0.001)。结论:p-Akt过表达伴随着PTEN表达缺失,两者与NSCLC侵袭、转移有关。     

P-170及多药耐药相关蛋白与食管鳞癌临床病理特征的关系

目的　研究多药耐药基因蛋白P - 170和多药耐药相关蛋白MRP在食管鳞状上皮癌中的表达 ,探讨其与食管鳞癌临床病理因素的关系及临床意义。方法　应用免疫组织化学S -P法检测 42例食管鳞状上皮癌组织中P - 170和MRP表达情况。结果　 42例食管癌组织中P - 170阳性表达率为80 .9% ,MRP阳性表达率为 6 9%。P - 170和MRP表达均与年龄 ,肿瘤大小 ,分化程度 ,浸润深度 ,临床分期无关。但在淋巴结转移者MRP阳性率为 86 .4% ,高于无淋巴结转移者 ( 5 0 % ) ,两者相比有显著性差异 (P <0 .0 5 )。结论　食管鳞癌组织中P - 170和MRP高表达可能是食管癌化疗效果不佳的重要原因之一 ,术后检测P - 170和MRP不仅对临床化疗方案的选择具有重要意义 ,同时MRP还可能对食管鳞癌预后的判断具有重要意义。     

PTEN signaling pathways in melanoma

Phosphatase and tensin homolog deleted in from chromosome ten (PTEN), initially also known as mutated in multiple advanced cancers or TGF-beta-regulated and epithelia cell-enriched phosphatase, is a tumor suppressor gene that is mutated in a large fraction of human melanomas. A broad variety of human cancers carry PTEN alterations, including glioblastomas, endometrial, breast, thyroid and prostate cancers. The PTEN protein has at least two biochemical functions: it has both lipid phosphatase and protein phosphatase activity. The lipid phosphatase activity of PTEN decreases intracellular PtdIns(3,4,5)P(3) level and downstream Akt activity. Cell-cycle progression is arrested at G1/S, mediated at least partially through the upregulation of the cyclin-dependent kinase inhibitor p27. In addition, agonist-induced apoptosis is mediated by PTEN, through the upregulation of proapoptotic machinery involving caspases and BID, and the downregulation of antiapoptotic proteins such as Bcl2. The protein phosphatase activity of PTEN is apparently less central to its involvement in tumorigenesis. It is involved in the inhibition of focal adhesion formation, cell spreading and migration, as well as the inhibition of growth factor-stimulated MAPK signaling. Therefore, the combined effects of the loss of PTEN lipid and protein phosphatase activity may result in aberrant cell growth and escape from apoptosis, as well as abnormal cell spreading and migration. In melanoma, PTEN loss has been mostly observed as a late event, although a dose-dependent loss of PTEN protein and function has been implicated in early stages of tumorigenesis as well. In addition, loss of PTEN and oncogenic activation of RAS seem to occur in a reciprocal fashion, both of which could cooperate with CDKN2A loss in contribution to melanoma tumorigenesis.     

PTEN signaling pathways in glioblastoma

Malignant gliomas are the most common primary brain tumor in adults, but the prognosis for patients with these tumors remains poor despite advances in diagnosis and standard therapies such as surgery, radiation therapy, and chemotherapy. Progress in the treatment of gliomas now depends to a great extent on an increased understanding of the biology of these tumors. Recent insights into the biology of gliomas include the finding that tyrosine kinase receptors and signal transduction pathways play a role in tumor initiation and maintenance. Deregulation of phosphatidylinositol 3-kinase (PI3K) signaling pathways resulting from genetic alterations in the PTEN tumor suppressor gene on 10q23 at the level of LOH, mutation and methylation have been identified in at least 60% of glioblastoma. Loss of PTEN function by mutation or LOH correlates with poor survival in anaplastic astrocytoma and glioblastoma, suggesting that PTEN plays a role in patient outcome. Interestingly, amplification of Epidermal growth factor receptor (EGFR) in the background of heterozygous PTEN knockout mice develop invasive glioma very similar to human glioblastoma, demonstrating the importance of PTEN in glioma progression and providing a model system to evaluate the efficacy of targeting PTEN in glioblastoma.     

Proteasome inhibitors can alter the signaling pathways and attenuate the P-glycoprotein-mediated multidrug resistance

Numerous signaling pathways were reported to be involved in the resistance for conventional cytotoxic drugs, although one of the main reasons is the overexpression of P-glycoprotein (P-gp) in multidrug resistant cancer cells. The overexpression of P-gp has been associated with the resistance to a wide range of anticancer drugs. Doxorubicin and paclitaxel are substrates of this transporter system and have an important role for the various human malignancies. In the present study, drug-sensitive MCF7 and multidrug resistant MCF7/ADR (characterized by overexpression of P-gp) human breast cancer cell lines were used as an experimental model. We have found that PS341 and MG132, proteasome inhibitors, reduced the degree of the multidrug resistance (MDR) in MCF7/ADR cells. This phenomenon was accompanied by a decrease in the IC50 value of doxorubicin and paclitaxel from 55.9 +/- 3.46 to 0.60 +/- 0.08 microM, and from 17.61 +/- 1.77 to 0.59 +/- 0.12 microM, respectively. The IC50 values of sensitive cells for doxorubicin and paclitaxel were about 0.42 and 0.83 microM, respectively. The effect of PS341 and MG132 on MCF7/ADR cells was associated with a significant decrease in both protein and gene levels of P-gp expression. Moreover, with regard to the expression of possible signal transduction pathways of mitogen-activated protein kinase (MAPK) related to the activation of mdr1, proteasome inhibitors did significantly influence the activation of these proteins. Western blot analysis revealed that 24 hr exposure of multidrug resistant MCF7/ADR cells with proteasome inhibitors did change the levels of DNA binding activity of nuclear factor-kappaB (NF-kappaB), pERK1/2, c-Jun, and p-c-Jun. In conclusion, we could remark that proteasome inhibitors (especially PS341) attenuate the resistance of MCF7/ADR cells for P-gp substrate drugs of doxorubicin and paclitaxel. Several proteins are supposed to be associated with the resensitization of the cells to conventional cytotoxic drugs, although decreased activity of P-gp is at least involved in the proteasome inhibitor-related resensitization. And influence with MAPK pathways, which have been reported to be associated with the regulation of P-gp, might be contributed to the resensitization brought by proteasome inhibitors.     

Notch信号通路与肿瘤

Notch信号通路存在于多种动物体内,脊椎动物中有4个Notch同源体Notch1、Notch2、Notch3、Notch4,其中Notch1在肿瘤形成中起重要作用,至于其是癌基因还是抑癌基因,目前尚存争议.Notch通路是许多重要细胞信号转导通路的交汇点,对Notch1的研究可进一步阐明肿瘤发生的机制,为肿瘤基因治疗及新药开发提供一个新的有希望的靶点.     

survivin基因与肿瘤多药耐药

肿瘤多药耐药是多种复杂机制共同作用的结果。大量研究表明survivin基因参与了细胞凋亡和细胞有丝分裂的调控,与肿瘤多耐药密切相关。     

caveolae与肿瘤细胞的多药耐药性

 caveolae是特化的细胞膜微结构域，它由其特异性的被覆蛋白caveolin及多种脂类分子和膜蛋白组成，在细胞外分子的内化、信号的跨膜转导和胆固醇的转运过程中起着重要的作用。新近的研究表明，caveolae及其某些组成成分在肿瘤多药耐药细胞中表达上调，并有可能参与了肿瘤细胞多药耐药性的形成。对caveolae与肿瘤细胞多药耐药性的研究进展进行了综述。     

肿瘤多药耐药的逆转措施

化疗是恶性肿瘤的主要治疗方法,而肿瘤多药耐药(MDR)是导致肿瘤化疗失败的重要原因之一.应用化学药物逆转剂、天然药物(中药)逆转剂、免疫治疗、基因治疗、纳米载体给药系统等逆转肿瘤MDR已取得初步进展.但研制出不良反应小、效果好、能够广泛应用于临床的逆转肿瘤MDR药物,仍需要更大努力.     

孕烷X受体与肿瘤多药耐药的相关性

 P-糖蛋白（P-gp）及其编码基因mdr1的过表达是肿瘤多药耐药（MDR）的经典机制。研究发现，孕烷X受体(PXR)可介导P-gp的表达，已证实PXR还具有抑制肿瘤细胞凋亡作用。因此，特异性地阻断PXR的活化可能是阻止MDR的新方法。     

P-glycoprotein,multidrug resistance and tumor progression

P-glycoprotein (Pgp) is a plasma membrane protein that was first characterised in multidrug resistant cell lines. The occurrence of Pgp in clinical tumors has been widely studied. Recent investigations have begun to focus on the relationship between Pgp detection in tumors and treatment outcome. In several types of tumors, detection of Pgp correlates with poor response to chemotherapy and shorter survival. P-glycoprotein overexpression often occurs upon relapse from chemotherapy but may also occur at the time of diagnosis. Studies of experimental rat liver carcinogenesis have shown that Pgp expression increases in late stages of carcinogenesis, suggesting that Pgp may be involved in tumor progression. While some of the Pgp isoforms are known to transport hydrophobic chemotherapeutic drugs out of tumor cells, the biologic effects of Pgp overexpression in tumor cells are not fully understood, because the spectrum of substrates for Pgp-mediated transport has not been determined. In the rat liver carcinoma model, strong expression of Pgp is associated with a highly vascular stroma, suggesting that Pgp in tumor cells may affect the connective tissue stroma. The regulation of Pgp appears to be complex, and little is known about how it is up-regulated during carcinogenesis. Further studies of the role of Pgp in malignancy may contribute to our understanding of molecular mechanisms which underlie tumor progression.