Structural, functional and therapeutic biology of survivin

Survivin is a unique member of the inhibitor of apoptosis (IAP) protein family that interferes with post-mitochondrial events including activation of caspases. Survivin regulates cell cycle also. It is expressed in most of the human tumors, but it is barely detectable in the terminally differentiated normal cells/tissues. Molecular mechanisms of regulation of survivin in cancer are not clearly understood. Nevertheless, the functional loss of wild type p53 is often associated with upregulation of survivin. Tumors that over-express survivin generally bear a poor prognosis and are associated with resistance to therapy. The differential expression of survivin in cancer versus normal tissues makes it a useful tool in cancer diagnosis and a promising therapeutic target. A growing body of literature suggests nuclear expression of survivin as a good prognostic marker. Disruption of the survivin induction pathway has resulted in an increase in apoptosis and inhibition of tumor growth. Regular therapies, such as, radiotherapy in combination with anticancer drugs in clinical practice may yield promising results.     

Ribozyme-mediated inhibition of survivin expression increases spontaneous and drug-induced apoptosis and decreases the tumorigenic potential of human prostate cancer cells

Survivin is a member of the inhibitor of apoptosis protein (IAP) family, which has been implicated in inhibition of apoptosis and control of mitotic progression. The finding that survivin is overexpressed in most human tumors but absent in normal adult tissues has led to the proposal of survivin as a promising therapeutic target for anticancer therapies. We decided to evaluate the effects of a ribozyme-based strategy for survivin inhibition in androgen-independent human prostate cancer cells. We constructed a Moloney-based retroviral vector expressing a ribozyme targeting the 3' end of the CUA(110) triplet in survivin mRNA, encoded as a chimeric RNA within adenoviral VA1 RNA. Polyclonal cell populations obtained by infection with the retroviral vector of two androgen-independent human prostate cancer cell lines (DU145 and PC-3) were selected for the study. Ribozyme-expressing prostate cancer cells were characterized by a significant reduction of survivin expression compared to parental cells transduced with a control ribozyme; the cells became polyploid, underwent caspase-9-dependent apoptosis and showed an altered pattern of gene expression, as detected by oligonucleotide array analysis. Survivin inhibition also increased the susceptibility of prostate cancer cells to cisplatin-induced apoptosis and prevented tumor formation when cells were xenografted in athymic nude mice. These findings suggest that manipulation of the antiapoptotic survivin pathway may provide a novel approach for the treatment of androgen-independent prostate cancer.     

Survivin beyond physiology: Orchestration of multistep carcinogenesis and therapeutic potentials

Survivin, a member of the inhibitor of apoptosis protein family, has been associated with protection from cell apoptosis and regulation of mitosis. Survivin exhibits low to undetectable expression in most finally differentiated adult tissues but is abundantly over-expressed in almost all cancers. The aberrant high expression of survivin in cancers is associated with advanced disease, increased rate of tumor recurrence, abbreviated overall survival and resistance to chemo- and radio- therapy. Survivin touches nearly every aspect of cancer and is involved in the initiation, maintenance and development of tumor. Therefore, its significance in cancer dictates the pursuit for anti-survivin cancer therapies.     

靶向survivin基因siRNA对宫颈癌细胞放射敏感性影响的实验 

 目的 探讨survivin表达对宫颈癌放射敏感性的影响。 方法 RT-PCR和Western blot法分析survivin基因mRNA和蛋白的表达, 平板集落形成实验检测细胞 增殖,流式细胞术检测细胞凋亡率。 survivin siRNA转染HeLa细胞,比较survivin siRNA对细胞凋亡、增殖以及放射敏感性的 影响。 结果 在宫颈癌HeLa细胞中存在survivin的表达,survivin siRNA可诱导HeLa细胞凋亡并抑制增殖 。 结论 survivin siRNA可通过影响细胞凋亡和增殖来增加HeLa细胞的放射敏感性     

Survivin expression and targeting in breast cancer

IntroductionSurvivin a multifunctional protein that controls cell division, inhibition of apoptosis and promotion of angiogenesis. It is expressed in most human neoplasm, but is absent in normal and differentiated tissues. The purpose of this article is to overview the expression of survivin, effect of its expression in response to treatment, correlation with other markers and newer advancement in targeting survivin.MethodsA detailed search of Medline was carried out using the following search strategy: “((survivin) OR ((apoptosis) AND (inhibitor OR inhibitors))) AND ((breast) AND (neoplasm OR neoplasms OR tumor OR tumor OR cancer OR carcinoma))”. Abstract of all articles thus identified were reviewed to identify the relevant studies, full articles of studies thus identified were then obtained and reviewed. All relevant data was extracted and tabulated.ResultsSurvivin expression by Immunohistochemistry was identified in 65.3% (55.2–90.0%) of the breast cancer patients among the identified studies while survivin mRNA by RT-PCR was identified in 93.6% (90–97%). Survivin expression has been reported to be associated with over expression of HER 2, vascular endothelial growth factor (VEGF), urokinase plasminogen activator (uPA)/PAI-1.ConclusionSurvivin is over expressed in majority of breast cancers. The over expression of survivin is found to correlate with HER 2 and EGFR expression. Survivin expression has been found to confer resistance to chemotherapy and radiation. Targeting survivin in experimental models improves survival. More studies are needed on the role of survivin in multi drug resistance (MDR) in the presence of Pgp/uPA/PAI-1 and the impact of survivin over expression in triple negative breast cancer.     

Survivin作为肿瘤生物标记的研究进展

Survivin是凋亡抑制蛋白家族的成员,不表达于终末分化的组织,然而在多数肿瘤组织中异常高表达。Survivin具有抑制细胞凋亡,调控细胞周期,促进细胞分化以及增强血管发生的多重作用。由于sur-vivin的复杂功能及其在肿瘤中特异性高表达的特性,其可以作为一个分子标记在肿瘤的早期诊断及判断病人预后等方面发挥重要作用。此外,survivin还与某些癌细胞的抗药性密切相关,因此survivin还可以作为预测病人对某些抗癌治疗反应的生物标记。     

人肺腺癌细胞株A549中HIF-1α对survivin的表达调控

背景与目的:survivin是一种重要的抗凋亡基因,在肿瘤组织中特异性高表达,并参与调控细胞周期和细胞凋亡,其高表达与肿瘤进展、药物抵抗以及预后关系密切。但survivin在肺癌中高表达的转录调控机制研究甚少。课题组前期研究成功构建含有survivin核心启动子的荧光报告载体pGL3-SVP230-luc,并发现核心启动子区存在缺氧诱导因子-1α(hypoxia-inducible factor-1α,HIF-1α)的潜在位点。本研究拟通过免疫荧光双标记法、电泳迁移率实验(EMSA)、共转染等方法探讨缺氧条件下人肺腺癌细胞株A549中HIF-1α调控survivin转录的确切机制。方法:⑴运用免疫荧光双标记检测缺氧A549细胞中HIF-1α与survivin的表达;⑵HIF-1α表达质粒和HIF-1αsiRNA分别转染A549细胞,30 h后RT-PCR、Western blot和免疫荧光双标法检测survivin mRNA和蛋白表达;⑶pGL3-SVP230-luc(含有survivin核心启动子的荧光报告载体)与HIF-1α表达质粒和HIF-1αsiRNA分别共转染A549细胞,测定萤光素酶的表达活性;⑷...     

The universal character of the tumor-associated antigen survivin.

Survivin is expressed in most human neoplasms, but is absent in normal, differentiated tissues. Survivin is a bifunctional inhibitor of apoptosis protein that has been implicated in protection from apoptosis and regulation of mitosis. Several clinical trials targeting survivin with a collection of different approaches from small molecule antagonists to immunotherapy are currently under way. With regard to the latter, spontaneous anti-survivin T-cell reactivity has been described in cancer patients suffering from a huge range of cancers of different origin, e.g., breast and colon cancer, lymphoma, leukemia, and melanoma. Thus, survivin may serve as a universal target antigen for anticancer immunotherapy. Accordingly, down-regulation of survivin as a means of immune escape would severely inflict the survival capacity of tumor cells, which highlights this protein as a prime target candidate for therapeutic vaccinations against cancer. Data from several ongoing phase I/II trials targeting survivin for patients with advanced cancer will provide further information about this idea.     

Survivin基因与细胞放射敏感性关系的研究进展

Survivin是凋亡抑制蛋白（inhibition of apoptosis protein,IAPs）家族的新成员,具有抑制细胞凋亡、调节细胞分裂、刺激肿瘤血管形成等作用。其在多数人类恶性肿瘤中特异性表达,而在正常组织中几无表达的特性使Survivin成为近年放射增敏研究的热点。Survivin与放射敏感性的关系及针对它的靶向治疗已在许多临床前研究中取得了令人惊喜的成果,有望成为放疗增敏领域的新靶点。     

Survivin splice variants regulate the balance between proliferation and cell death

Survivin is an inhibitor of apoptosis protein that also plays critical roles in regulating the cell cycle and mitosis. Its prominent expression in essentially all human malignancies, and low or absent expression in most normal tissues, suggests that it would be an ideal target for cancer-directed therapy. Impeding development of safe and effective survivin antagonists for clinical use is a lack of understanding of the molecular mechanisms by which survivin differentially affects apoptosis and cell division, in normal and malignant cells. We show that the diverse functional roles of survivin can be explained, in part, by its heterodimerization with survivin splice variants in tumor cells. Survivin and survivin-DeltaEx3 interact within the mitochondria where they may inhibit mitochondrial-dependent apoptosis. If the expression of all survivin forms is eliminated by siRNA transfections, cells undergo both apoptosis and defective cell division. Overall, we provide new insights suggesting that targeting specific survivin isoforms, rather than survivin alone, may selectively and effectively destroy tumor cells. These findings are likely to have a significant impact in the design of biologic agents for clinical therapy.     

Survivin与肿瘤转移

Survivin是一种新型凋亡抑制因子,近年来不断发现其在肿瘤组织中表达,并与肿瘤转移和预后密切相关,成为新的研究热点,同时也为肿瘤转移靶向治疗提供了全新的方向。     

Impacting tumor cell-fate by targeting the inhibitor of apoptosis protein survivin

Survivin (BIRC5), a member of the inhibitor of apoptosis protein (IAP) family that inhibits caspases and blocks cell death is highly expressed in cancer and is associated with a poorer clinical outcome. Functioning simultaneously during cell division and apoptosis inhibition, survivin plays a pivotal role in determining cell survival. Survivin has consistently been identified by molecular profiling analysis to be associated with higher tumor grade, more advanced disease, abbreviated survival, accelerated rates of recurrence, and chemotherapy and radiation resistance. Survivin's differential expression in cancer compared to normal tissue and its role as a nodal protein in a number of cellular pathways make it a highly flexible therapeutic target, suitable for small-molecule inhibitiors, molecular antagonists, and vaccination-based therapies. By targeting survivin it is hoped that multiple tumor signaling circuitries may be simultaneously disabled. This effect may be applicable to many tumor histologies irrespective of specific genetic makeup. To date, survivin inhibitors have shown modest activity as single agents, but it is anticipated that when given in combination with cytotoxic chemotherapy or monoclonal antibodies they may exhibit enhanced efficacy. This review discusses the complex circuitry of survivin in human cancers and highlights clinical trials involving novel agents that target this important protein.     

Downregulation of survivin expression by induction of the effector cell protease receptor-1 reduces tumor growth potential and results in an increased sensitivity to anticancer agents in human colon cancer

Survivin, a novel inhibitor of apoptosis, is expressed in cancer cells and not in normal adult tissues, and is recognised as a potential target in anticancer therapy. The induction of a natural antisense of survivin, effector cell protease receptor-1 (EPR-1), in a human colon cancer cell line resulted in a downregulation of survivin expression, with a similar decrease in cell proliferation, an increase in apoptosis and an increase in the sensitivity to anticancer agents. In addition, subcutaneous (s.c.) tumours from EPR-1 transfectants showed a significant reduction in size compared with parental cells, and this antitumour efficacy was further enhanced in combination with anticancer agents. These findings suggest that regulation of survivin by the induction of EPR-1 cDNA may have significant potential as a therapy for human colon cancer.     

宫颈癌中survivin的表达及临床意义

 目的　探讨调亡抑制基因survivin在宫颈癌组织中的表达及临床意义。方法　应用免疫组化方法检测survivin和cyclinB1蛋白在 5 6例宫颈癌和 18例正常宫颈组织中的表达 ,并将结果进行了相关分析。结果　 6 9.6 % (39/5 6 )宫颈癌中表达survivin基因 ,而在正常宫颈组织为 16 .7% (3/18) (P <0 .0 1) ;survivin基因表达与宫颈癌组织细胞类型及分化程度无明显相关关系 ,但与年龄、临床分期和淋巴结转移有关。宫颈癌组织中cyclinB1表达与survivin表达显著相关。 结论　cyclinB1和survivin在细胞周期中有协同作用 ,它们的过度表达可能是宫颈癌癌细胞G2 /M过渡的促进因素。survivin基因有可能成为宫颈癌基因治疗的靶点。     

Development of a novel gene therapy using survivin antisense expressing adenoviral vectors

BACKGROUND: Survivin, a novel inhibitor of apoptosis, is undetectable in normal adult tissues but becomes notably expressed in the most common human cancers, and is recognized as a potential target in anticancer therapy. METHODS: In this study we evaluated a survivin antisense expressing replication-incompetent adenoviral vector under the control of the cytomegalovirus promoter (pAd.CMV-SAS) for cytoreductive effects in human HT-29 colon cancer cells in vitro and in vivo. RESULTS: Infection of tumor cells with pAd.CMV-SAS caused down-regulation of survivin expression and the potential for spontaneous apoptosis in tumor cells. In contrast, pAd.CMV-SAS did not affect cell viability of normal human cells including fibroblasts. In addition, infection of tumor cells with pAd.CMV-SAS resulted in an increase of the G0/G1 phase population in the cell cycle, and increased their sensitivity to chemotherapeutic drugs in vitro. The efficacies of pAd.CMV-SAS were inversely correlated with survivin expression level. In nude mice, pAd.CMV-SAS suppressed tumor formation, as well as decreased the tumor volumes to approximately 30% of the control tumors. Furthermore, it was confirmed that the anti-tumor efficacy of pAd.CMV-SAS was also enhanced in combination with chemotherapeutic drugs in vivo. CONCLUSIONS: These findings suggest that targeting of survivin using adenoviral antisense vectors may have a potential role in the selective therapy of colon cancer.