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Journal of Cell Science Apr 2019Survivin (also known as BIRC5) is an evolutionarily conserved eukaryotic protein that is essential for cell division and can inhibit cell death. Normally it is only... (Review)
Review
Survivin (also known as BIRC5) is an evolutionarily conserved eukaryotic protein that is essential for cell division and can inhibit cell death. Normally it is only expressed in actively proliferating cells, but is upregulated in most, if not all cancers; consequently, it has received significant attention as a potential oncotherapeutic target. In this Cell Science at a Glance article and accompanying poster, we summarise our knowledge of survivin 21 years on from its initial discovery. We describe the structure, expression and function of survivin, highlight its interactome and conclude by describing anti-survivin strategies being trialled.
Topics: Apoptosis; Humans; Mitosis; Molecular Targeted Therapy; Neoplasms; Survivin
PubMed: 30948431
DOI: 10.1242/jcs.223826 -
Viruses Dec 2021Gene therapy is currently in the public spotlight. Several gene therapy products, including oncolytic virus (OV), which predominantly replicates in and kills cancer... (Review)
Review
Gene therapy is currently in the public spotlight. Several gene therapy products, including oncolytic virus (OV), which predominantly replicates in and kills cancer cells, and COVID-19 vaccines have recently been commercialized. Recombinant adenoviruses, including replication-defective adenoviral vector and conditionally replicating adenovirus (CRA; oncolytic adenovirus), have been extensively studied and used in clinical trials for cancer and vaccines. Here, we review the biology of wild-type adenoviruses, the methodological principle for constructing recombinant adenoviruses, therapeutic applications of recombinant adenoviruses, and new technologies in pluripotent stem cell (PSC)-based regenerative medicine. Moreover, this article describes the technology platform for efficient construction of diverse "CRAs that can specifically target tumors with multiple factors" (m-CRAs). This technology allows for modification of four parts in the adenoviral E1 region and the subsequent insertion of a therapeutic gene and promoter to enhance cancer-specific viral replication (i.e., safety) as well as therapeutic effects. The screening study using the m-CRA technology successfully identified survivin-responsive m-CRA (Surv.m-CRA) as among the best m-CRAs, and clinical trials of Surv.m-CRA are underway for patients with cancer. This article also describes new recombinant adenovirus-based technologies for solving issues in PSC-based regenerative medicine.
Topics: Adenoviridae; Adenoviridae Infections; Animals; COVID-19; COVID-19 Vaccines; Cell Line, Tumor; Gene Expression; Genetic Therapy; Genetic Vectors; Humans; Immunotherapy; Oncolytic Viruses; Pluripotent Stem Cells; Promoter Regions, Genetic; SARS-CoV-2; Survivin; Virus Replication
PubMed: 34960772
DOI: 10.3390/v13122502 -
The Journal of Clinical Investigation Dec 2023Patients with inflammatory bowel disease (IBD) are susceptible to colitis-associated cancer (CAC). Chronic inflammation promotes the risk for CAC. In contrast, mucosal...
Patients with inflammatory bowel disease (IBD) are susceptible to colitis-associated cancer (CAC). Chronic inflammation promotes the risk for CAC. In contrast, mucosal healing predicts improved prognosis in IBD and reduced risk of CAC. However, the molecular integration among colitis, mucosal healing, and CAC remains poorly understood. Claudin-2 (CLDN2) expression is upregulated in IBD; however, its role in CAC is not known. The current study was undertaken to examine the role for CLDN2 in CAC. The AOM/DSS-induced CAC model was used with WT and CLDN2-modified mice. High-throughput expression analyses, murine models of colitis/recovery, chronic colitis, ex vivo crypt culture, and pharmacological manipulations were employed in order to increase our mechanistic understanding. The Cldn2KO mice showed significant inhibition of CAC despite severe colitis compared with WT littermates. Cldn2 loss also resulted in impaired recovery from colitis and increased injury when mice were subjected to intestinal injury by other methods. Mechanistic studies demonstrated a possibly novel role of CLDN2 in promotion of mucosal healing downstream of EGFR signaling and by regulation of Survivin expression. An upregulated CLDN2 expression protected from CAC and associated positively with crypt regeneration and Survivin expression in patients with IBD. We demonstrate a potentially novel role of CLDN2 in promotion of mucosal healing in patients with IBD and thus regulation of vulnerability to colitis severity and CAC, which can be exploited for improved clinical management.
Topics: Animals; Humans; Mice; Claudin-2; Colitis; Colitis-Associated Neoplasms; Dextran Sulfate; Disease Models, Animal; Inflammatory Bowel Diseases; Intestinal Mucosa; Mice, Inbred C57BL; Survivin
PubMed: 37815870
DOI: 10.1172/JCI170771 -
Journal of Clinical Oncology : Official... Mar 2023Despite intensive treatment with surgery, radiation therapy, temozolomide (TMZ) chemotherapy, and tumor-treating fields, mortality of newly diagnosed glioblastoma (nGBM)... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Despite intensive treatment with surgery, radiation therapy, temozolomide (TMZ) chemotherapy, and tumor-treating fields, mortality of newly diagnosed glioblastoma (nGBM) remains very high. SurVaxM is a peptide vaccine conjugate that has been shown to activate the immune system against its target molecule survivin, which is highly expressed by glioblastoma cells. We conducted a phase IIa, open-label, multicenter trial evaluating the safety, immunologic effects, and survival of patients with nGBM receiving SurVaxM plus adjuvant TMZ following surgery and chemoradiation (ClinicalTrials.gov identifier: NCT02455557).
METHODS
Sixty-four patients with resected nGBM were enrolled including 38 men and 26 women, in the age range of 20-82 years. Following craniotomy and fractionated radiation therapy with concurrent TMZ, patients received four doses of SurVaxM (500 μg once every 2 weeks) in Montanide ISA-51 plus sargramostim (granulocyte macrophage colony-stimulating factor) subcutaneously. Patients subsequently received adjuvant TMZ and maintenance SurVaxM concurrently until progression. Progression-free survival (PFS) and overall survival (OS) were reported. Immunologic responses to SurVaxM were assessed.
RESULTS
SurVaxM plus TMZ was well tolerated with no serious adverse events attributable to SurVaxM. Of the 63 patients who were evaluable for outcome, 60 (95.2%) remained progression-free 6 months after diagnosis (prespecified primary end point). Median PFS was 11.4 months and median OS was 25.9 months measured from first dose of SurVaxM. SurVaxM produced survivin-specific CD8+ T cells and antibody/immunoglobulin G titers. Apparent clinical benefit of SurVaxM was observed in both methylated and unmethylated patients.
CONCLUSION
SurVaxM appeared to be safe and well tolerated. The combination represents a promising therapy for nGBM. For patients with nGBM treated in this manner, PFS may be an acceptable surrogate for OS. A large randomized clinical trial of SurVaxM for nGBM is in progress.
Topics: Male; Humans; Female; Young Adult; Adult; Middle Aged; Aged; Aged, 80 and over; Temozolomide; Glioblastoma; Survivin; Antineoplastic Agents, Alkylating; Brain Neoplasms; Adjuvants, Immunologic; Vaccines, Subunit
PubMed: 36521103
DOI: 10.1200/JCO.22.00996 -
Cancer Communications (London, England) Dec 2019High-grade glioma (HGG) is a fatal human cancer. Bortezomib, a proteasome inhibitor, has been approved for the treatment of multiple myeloma but its use in glioma awaits...
BACKGROUND
High-grade glioma (HGG) is a fatal human cancer. Bortezomib, a proteasome inhibitor, has been approved for the treatment of multiple myeloma but its use in glioma awaits further investigation. This study aimed to explore the chemotherapeutic effect and the underlying mechanism of bortezomib on gliomas.
METHODS
U251 and U87 cell viability and proliferation were detected by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay, tumor cell spheroid growth, and colony formation assay. Cell apoptosis and cell cycle were detected by flow cytometry. Temozolomide (TMZ)-insensitive cell lines were induced by long-term TMZ treatment, and cells with stem cell characteristics were enriched with stem cell culture medium. The mRNA levels of interested genes were measured via reverse transcription-quantitative polymerase chain reaction, and protein levels were determined via Western blotting/immunofluorescent staining in cell lines and immunohistochemical staining in paraffin-embedded sections. Via inoculating U87 cells subcutaneously, glioma xenograft models in nude mice were established for drug experiments. Patient survival data were analyzed using the Kaplan-Meier method.
RESULTS
Bortezomib inhibited the viability and proliferation of U251 and U87 cells in a dose- and time-dependent manner by inducing apoptosis and cell cycle arrest. Bortezomib also significantly inhibited the spheroid growth, colony formation, and stem-like cell proliferation of U251 and U87 cells. When administrated in combination, bortezomib showed synergistic effect with TMZ in vitro and sensitized glioma to TMZ treatment both in vitro and in vivo. Bortezomib reduced both the mRNA and protein levels of Forkhead Box M1 (FOXM1) and its target gene Survivin. The FOXM1-Survivin axis was markedly up-regulated in established TMZ-insensitive glioma cell lines and HGG patients. Expression levels of FOXM1 and Survivin were positively correlated with each other and both related to poor prognosis in glioma patients.
CONCLUSIONS
Bortezomib was found to inhibit glioma growth and improved TMZ chemotherapy efficacy, probably via down-regulating the FOXM1-Survivin axis. Bortezomib might be a promising agent for treating malignant glioma, alone or in combination with TMZ.
Topics: Adolescent; Adult; Aged; Animals; Antineoplastic Agents; Apoptosis; Bortezomib; Brain Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Survival; Down-Regulation; Female; Forkhead Box Protein M1; Gene Expression Regulation, Neoplastic; Glioma; Humans; Male; Mice, Inbred BALB C; Mice, Nude; Middle Aged; Survivin; Temozolomide; Young Adult
PubMed: 31796105
DOI: 10.1186/s40880-019-0424-2 -
Science Advances Mar 2020Small interfering RNA (siRNA) is a powerful tool for gene silencing that has been used for a wide range of biomedical applications, but there are many challenges facing...
Small interfering RNA (siRNA) is a powerful tool for gene silencing that has been used for a wide range of biomedical applications, but there are many challenges facing its therapeutic use in vivo. Here, we report on a platelet cell membrane-coated metal-organic framework (MOF) nanodelivery platform for the targeted delivery of siRNA in vivo. The MOF core is capable of high loading yields, and its pH sensitivity enables endosomal disruption upon cellular uptake. The cell membrane coating provides a natural means of biointerfacing with disease substrates. It is shown that high silencing efficiency can be achieved in vitro against multiple target genes. Using a murine xenograft model, significant antitumor targeting and therapeutic efficacy are observed. Overall, the biomimetic nanodelivery system presented here provides an effective means of achieving gene silencing in vivo and could be used to expand the applicability of siRNA across a range of disease-relevant applications.
Topics: Animals; Blood Platelets; Cell Line, Tumor; Cell Membrane; Coated Vesicles; Drug Carriers; Gene Knockdown Techniques; Gene Silencing; Gene Transfer Techniques; Genes, Reporter; Humans; Metal Nanoparticles; Metal-Organic Frameworks; Mice; RNA, Small Interfering; Survivin; Xenograft Model Antitumor Assays
PubMed: 32258408
DOI: 10.1126/sciadv.aaz6108 -
Proceedings of the National Academy of... Aug 2021To identify regulators of triple-negative breast cancer (TNBC), gene expression profiles of malignant parts of TNBC (mTNBC) and normal adjacent (nadj) parts of the same...
To identify regulators of triple-negative breast cancer (TNBC), gene expression profiles of malignant parts of TNBC (mTNBC) and normal adjacent (nadj) parts of the same breasts have been compared. We are interested in the roles of estrogen receptor β (ERβ) and the cytochrome P450 family (CYPs) as drivers of TNBC. We examined by RNA sequencing the mTNBC and nadj parts of five women. We found more than a fivefold elevation in mTNBC of genes already known to be expressed in TNBC: BIRC5/survivin, Wnt-10A and -7B, matrix metalloproteinases (MMPs), chemokines, anterior gradient proteins, and lysophosphatidic acid receptor and the known basal characteristics of TNBC, sox10, ROPN1B, and Col9a3. There were two unexpected findings: 1) a strong induction of CYPs involved in activation of fatty acids (CYP4), and in inactivation of calcitriol (CYP24A1) and retinoic acid (CYP26A1); and 2) a marked down-regulation of FOS, FRA1, and JUN, known tethering partners of ERβ. ERβ is expressed in 20 to 30% of TNBCs and is being evaluated as a target for treating TNBC. We used ERβ TNBC patient-derived xenografts in mice and found that the ERβ agonist LY500703 had no effect on growth or proliferation. Expression of CYPs was confirmed by immunohistochemistry in formalin-fixed and paraffin-embedded (FFPE) TNBC. In TNBC cell lines, the CYP4Z1-catalyzed fatty acid metabolite 20-hydroxyeicosatetraenoic acid (20-HETE) increased proliferation, while calcitriol decreased proliferation but only after inhibition of CYP24A1. We conclude that CYP-mediated pathways can be drivers of TNBC but that ERβ is unlikely to be a tumor suppressor because the absence of its main tethering partners renders ERβ functionless on genes involved in proliferation and inflammation.
Topics: Amphibian Proteins; Animals; Benzopyrans; Calcitriol; Cytochrome P-450 Enzyme System; Down-Regulation; Estrogen Receptor alpha; Estrogen Receptor beta; Fatty Acids; Female; Gene Expression Regulation, Neoplastic; Humans; Mice; Neoplasms, Experimental; Random Allocation; Survivin; Transcriptome; Tretinoin; Triple Negative Breast Neoplasms; Wnt Proteins
PubMed: 34389675
DOI: 10.1073/pnas.2104162118 -
Life Sciences Aug 2024Inhibitors of Apoptosis proteins (IAPs) were discovered through experiments aimed at rescuing apoptosis in insects. Classically associated with the inhibition of... (Review)
Review
Inhibitors of Apoptosis proteins (IAPs) were discovered through experiments aimed at rescuing apoptosis in insects. Classically associated with the inhibition of apoptosis, the IAP member Survivin also regulates cell cycle progression and is an essential component of the Chromosomal Passenger Complex (CPC), responsible for chromosomal segregation. Although undetectable in most adult tissues, Survivin is expressed in Adult Stem Cells (ASCs) and plays a crucial role in their maintenance. Survivin is overexpressed in most cancers, contributing to their clonal expansion. As a result, it has been proposed as a possible anticancer target for nearly two decades. In this discussion, we will explore the rationale behind Survivin as a therapeutic target, focusing on common cancer types such as carcinomas, sarcomas, and leukemias. We will delve into the modulation of Survivin by cancer pro-survival cell signaling, the association between SNPs and tumorigenesis, and its regulation by miRNAs. Finally, we will compare cell growth, clonogenic capacity, and apoptosis, along with different strategies for Survivin inhibition, including gene expression and protein activity modulation.
Topics: Humans; Survivin; Neoplasms; Animals; Inhibitor of Apoptosis Proteins; Apoptosis; MicroRNAs
PubMed: 38848940
DOI: 10.1016/j.lfs.2024.122788 -
The Indian Journal of Medical Research Apr 2015Survivin, a member of the inhibitor of apoptosis (IAP) protein family that inhibits caspases and blocks cell death, is highly expressed in most cancers and is associated... (Review)
Review
Survivin, a member of the inhibitor of apoptosis (IAP) protein family that inhibits caspases and blocks cell death, is highly expressed in most cancers and is associated with a poor clinical outcome. Survivin has consistently been identified by molecular profiling analysis to be associated with high tumour grade cancers, different disease survival and recurrence. Polymorphisms in the survivin gene are emerging as powerful tools to study the biology of the disease and have the potential to be used in disease prognosis and diagnosis. The survivin gene polymorphisms have also been reported to influence tumour aggressiveness as well as survival of cancer patients. The differential expression of survivin in cancer cells compared to normal tissues and its role as a nodal protein in a number of cellular pathways make it a high target for different therapeutics. This review discusses the complex circuitry of survivin in human cancers and gene variants of survivin, and highlights novel therapy that targets this important protein.
Topics: Apoptosis; Biomarkers, Tumor; Gene Expression Regulation, Neoplastic; Humans; Inhibitor of Apoptosis Proteins; Molecular Targeted Therapy; Neoplasms; Polymorphism, Single Nucleotide; Survivin
PubMed: 26112839
DOI: 10.4103/0971-5916.159250 -
Medicinal Research Reviews May 2019Survivin is a small protein that belongs to the inhibitor of apoptosis protein family. It is abundantly expressed in tumors compared with adult differentiated tissues,... (Review)
Review
Survivin is a small protein that belongs to the inhibitor of apoptosis protein family. It is abundantly expressed in tumors compared with adult differentiated tissues, being associated with poor prognosis in many human neoplasms. This apoptotic inhibitor has a relevant role in both the promotion of cancer cell survival and in the inhibition of cell death. Consequently, aberrant survivin expression stimulates tumor progression and confers resistance to several therapeutic strategies in a variety of tumors. In fact, efficient survivin downregulation or inhibition results in spontaneous apoptosis or sensitization to chemotherapy and radiotherapy. Therefore, all these features make survivin an attractive therapeutic target to treat cancer. Currently, there are several survivin inhibitors under clinical evaluation, although more specific and efficient survivin inhibitors are being developed. Moreover, novel combination regimens targeting survivin together with other therapeutic approaches are currently being designed and assessed. In this review, recent progress in the therapeutic options targeting survivin for cancer treatment is analyzed. Direct survivin inhibitors and their current development status are explored. Besides, the major signaling pathways implicated in survivin regulation are described and different therapeutic approaches involving survivin indirect inhibition are evaluated. Finally, promising novel inhibitors under preclinical or clinical evaluation as well as challenges of developing survivin inhibitors as a new therapy for cancer treatment are discussed.
Topics: Antineoplastic Agents; Cell Differentiation; Humans; Molecular Targeted Therapy; Neoplasms; Signal Transduction; Survivin
PubMed: 30421440
DOI: 10.1002/med.21547