Survivin In Cancer Research Articles

Role of Survivin in Bladder Cancer: Issues to Be Overcome When Designing an Efficient Dual Nano-Therapy.

Bladder cancer is the 10th most diagnosed cancer, with almost 10 M cancer deaths last year worldwide. Currently, chemotherapy is widely used as adjuvant therapy after surgical transurethral resection. Paclitaxel (PTX) is one of the most promising drugs, but cancer cells acquire resistance, causing failure of this treatment and increasing the recurrence of the disease. This poor chemotherapeutic response has been associated with the overexpression of the protein survivin. In this work, we present a novel dual nano-treatment for bladder cancer based on the hypothesis that the inhibition of survivin in cancer cells, using a siRNA gene therapy strategy, could decrease their resistance to PTX. For this purpose, two different polymeric nanoparticles were developed to encapsulate PTX and survivin siRNA independently. PTX nanoparticles showed sizes around 150 nm, with a paclitaxel loading of around 1.5%, that produced sustained tumor cell death. In parallel, siRNA nanoparticles, with similar sizes and loading efficiency of around 100%, achieved the oligonucleotide transfection and knocking down of survivin expression that also resulted in tumor cell death. However, dual treatment did not show the synergistic effect expected. The root cause of this issue was found to be the cell cycle arrest produced by nuclear survivin silencing, which is incompatible with PTX action. Therefore, we concluded that although the vastly reported role of survivin in bladder cancer, its silencing does not sensitize cells to currently applied chemotherapies.

Subcellular Compartmentalization of Survivin is Associated with Biological Aggressiveness and Prognosis in Prostate Cancer

The role of subcellular survivin compartmentalization in the biology and prognosis of prostate cancer is unclear. We therefore investigated subcellular localization of survivin in more than 3000 prostate cancer patients by quantitative immunohistochemistry and performed transcriptomics of 250 prostate cancer patients and healthy donors using publicly available datasets. Survivin (BIRC5) gene expression was increased in primary prostate cancers and metastases, but did not differ in recurrent vs non-recurrent prostate cancers. Survivin immunohistochemistry (IHC) staining was limited exclusively to the nucleus in 900 prostate cancers (40.0%), and accompanied by various levels of cytoplasmic positivity in 1338 tumors (59.4%). 0.5% of prostate cancers did not express survivin. Nuclear and cytoplasmic survivin staining intensities were strongly associated with each other, pT category, and higher Gleason scores. Cytoplasmic but not nuclear survivin staining correlated with high tumor cell proliferation in prostate cancers. Strong cytoplasmic survivin staining, but not nuclear staining predicted an unfavorable outcome in univariate analyses. Multivariate Cox regression analysis showed that survivin is not an independent prognostic marker. In conclusion, we provide evidence that survivin expression is increased in prostate cancers, especially in metastatic disease, resulting in higher aggressiveness and tumor progression. In addition, subcellular compartmentalization is an important aspect of survivin cancer biology, as only cytoplasmic, but not nuclear survivin accumulation is linked to biological aggressiveness and prognosis of prostate cancers.

Trace of survivin in cancer.

Survivin is one of the most cancer-specific proteins overexpressed in almost all malignancies, but is nearly undetectable in most normal tissues in adults. Functionally, as a member of the inhibitor of apoptosis family, survivin has been shown to inhibit apoptosis and increase proliferation. The antiapoptotic function of survivin seems to be related to its ability to inhibit caspases directly or indirectly. Furthermore, the role of survivin in cell cycle division control is related to its role in the chromosomal passenger complex. Consistent with its determining role in these processes, survivin plays a crucial role in cancer progression and cancer cell resistance to anticancer drugs and ionizing radiation. On the basis of these findings, recently survivin has been investigated intensively as an ideal tumor biomarker. Thus, multiple molecular approaches such as use of the RNA interfering technique, antisense oligonucleotides, ribozyme, and small molecule inhibitors have been used to downregulate survivin regulation and inhibit its biological function consequently. In this review, all these approaches are explained and other compounds that induced apoptosis in different cell lines through survivin inhibition are also reported.

DNA-Functionalized Dye-Loaded Polymeric Nanoparticles: Ultrabright FRET Platform for Amplified Detection of Nucleic Acids.

Going beyond the limits of optical biosensing motivates exploration of signal amplification strategies that convert a single molecular recognition event into a response equivalent to hundreds of fluorescent dyes. In this respect, Førster Resonance Energy Transfer (FRET) with bright fluorescent nanoparticles (NPs) is an attractive direction, but it is limited by poor efficiency of NPs as FRET donors, because their size is typically much larger than the Førster radius (∼5 nm). Here, we established FRET-based nanoparticle probes that overcome this fundamental limitation by exploiting a phenomenon of giant light harvesting with thousands of strongly coupled dyes in a polymer matrix. These nanoprobes are based on 40 nm dye-loaded poly(methyl methacrylate- co-methacrylic acid) (PMMA-MA) NPs, so-called light-harvesting nanoantennas, which are functionalized at their surface with oligonucleotides. To achieve this functionalization, we developed an original methodology: PMMA-MA was modified with azide/carboxylate bifunctional group that enabled assembly of small polymeric NPs and their further Cu-free click coupling with oligonucleotides. The obtained functionalized nanoantenna behaves as giant energy donor, where hybridization of target nucleic acid (encoding survivin cancer marker) with ∼23 grafted oligonucleotides/Cy5-acceptors switches on/off FRET from ∼3200 rhodamine-donors of the nanoantenna, leading to 75-fold signal amplification. In solution and on surfaces at single-particle level, the nanoprobe provides sequence-specific two-color ratiometric response to nucleic acids with limit of detection reaching 0.25 pM. It displays unprecedented brightness for a FRET biosensor: it outperforms analogous FRET-based molecular probe by >2000-fold and QDot-605 by ∼100-fold. The developed concept of amplified sensing will increase orders of magnitude sensitivity of fluorescent probes for biomolecular targets.

Differentially localized survivin and STAT3 as markers of gastric cancer progression: Association with Helicobacter pylori.

Localization and differential expression of STAT3 and survivin in cancer cells are often related to distinct cellular functions. The involvement of survivin and STAT3 in gastric cancer has been reported in separate studies but without clear understanding of their kinetics in cancer progression. We examined intracellular distribution of STAT3 and survivin in gastric adenocarcinoma and compared it with normal and precancer tissues using immunoblotting and immunohistochemistry. Analysis of a total of 156 gastric samples comprising 61 histologically normal, 30 precancerous tissues (comprising intestinal metaplasia and dysplasia), and 65 adenocarcinomas, collected as endoscopic biopsies from treatment naïve study participants, revealed a significant (P<.001) increase in overall protein levels. Survivin expression was detectable in both cytoplasmic (90.8%) and nuclear (87.7%) compartments in gastric adenocarcinomas lesions. Precancerous dysplastic gastric lesions exhibited a moderate survivin expression (56.7%) localized in cytoplasmic compartment. Similarly, STAT3 and pSTAT3 expression was detected at high level in gastric cancer lesions. The levels of compartmentalized expression of survivin and STAT3/pSTAT3 correlated in precancerous and adenocarcinoma lesions. Although overexpression of these proteins was found associated with the tobacco use and alcohol consumption, their expression invariably and strongly correlated with concurrent Helicobacter pylori infection. Receiver operating characteristic analysis of nuclear survivin, STAT3, and pSTAT3 in different study groups showed acceptable positive and negative predictive values with area under the curve above 0.8 (P<.001). Overall, our results suggest that overall increase in survivin and STAT3 and their subcellular localization are key determinants of gastric cancer progression, which can be collectively used as potential disease biomarkers and therapeutic targets for gastric cancer.

The twisted survivin connection to angiogenesis.

Survivin, a member of the inhibitor of apoptosis family of proteins (IAPs) that controls cell division, apoptosis, metastasis and angiogenesis, is overexpressed in essentially all human cancers. As a consequence, the gene/protein is considered an attractive target for cancer treatment. Here, we discuss recent findings related to the regulation of survivin expression and its role in angiogenesis, particularly in the context of hypoxia. We propose a novel role for survivin in cancer, whereby expression of the protein in tumor cells promotes VEGF synthesis, secretion and angiogenesis. Mechanistically, we propose the existence of a positive feed-back loop involving PI3-kinase/Akt activation and enhanced β-Catenin-TCF/LEF-dependent VEGF expression followed by secretion. Finally, we elaborate on the possibility that this mechanism operating in cancer cells may contribute to enhanced tumor vascularization by vasculogenic mimicry together with conventional angiogenesis.

Survivin: A molecular biomarker in cancer.

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.

Identification of novel helper epitope peptides of Survivin cancer-associated antigen applicable to developing helper/killer-hybrid epitope long peptide cancer vaccine

We identified novel helper epitope peptides of Survivin cancer antigen, which are presented to both HLA-DRB1*01:01 and DQB1*06:01. The helper epitope also contained three distinct Survivin-killer epitopes presented to HLA-A*02:01 and A*24:02. This 19 amino-acids epitope peptide (SU18) induced weak responses of Survivin-specific CD4+ and CD8+ T cells though it contained both helper and killer epitopes. To enhance the vaccine efficacy, we synthesized a long peptide by conjugating SU18 peptide and another DR53-restricted helper epitope peptide (SU22; 12 amino-acids) using glycine-linker. We designated this artificial 40 amino-acids long peptide containing two helper and three killer epitopes as Survivin-helper/killer-hybrid epitope long peptide (Survivin-H/K-HELP). Survivin-H/K-HELP allowed superior activation of IFN-γ-producing CD4+ Th1 cells and CD8+ Tc1 cells compared with the mixture of its component peptides (SU18 and SU22) in the presence of OK-432-treated monocyte-derived DC (Mo-DC). Survivin-H/K-HELP-pulsed Mo-DC pretreated with OK-432 also exhibited sustained antigen-presentation capability of stimulating Survivin-specific Th1 cells compared with Mo-DC pulsed with a mixture of SU18 and SU22 short peptides. Moreover, we demonstrated that Survivin-H/K-HELP induced a complete response in a breast cancer patient with the induction of cellular and humoral immune responses. Thus, we believe that an artificially synthesized Survivin-H/K-HELP will become an innovative cancer vaccine.

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.

Relationship between Survivin and gastric cancer

Relationship between Survivin and gastric cancer

Targeting Survivin in Cancer: Novel Drug Development Approaches

Survivin is a well-established target in experimental cancer therapy. The molecule is over-expressed in most human tumors, but hardly detectable in normal tissues. Multiple functions in different subcellular compartments have been assigned. It participates in the control of cell division, apoptosis, the cellular stress response, and also in the regulation of cell migration and metastasis. Survivin expression has been recognized as a biomarker: high expression indicates an unfavorable prognosis and resistance to chemotherapeutic agents and radiation treatment. Survivin is an unconventional drug target and several indirect approaches have been exploited to affect its function and the phenotype of survivin-expressing cells. Interference with the expression of the survivin gene, the utilization of its messenger RNA, the intracellular localization, the interaction with binding partners, the stability of the survivin protein, and the induction of survivin-specific immune responses have been taken into consideration. A direct strategy to inhibit survivin has been based on the identification of a specifically interacting peptide. This peptide can recognize survivin intracellularly and cause the degradation of the ligand–survivin complex. Technology is being developed that might allow the derivation of small molecular-weight, drug-like compounds that are functionally equivalent to the peptide ligand.

AOSP25 EXPRESSION OF SURVIVIN, FAS, CYCLIN E, AND CASPASE-3 IN APOPTOTIC BREAST CANCER CELLS INDUCED BY ELECTROCHEMICAL THERAPY

s, 5th AOS and 9th Annual Conference of OOTR, 2013 / European Journal of Cancer 49S1 (2013) S1−S22 S15 Discussion. Polz expression can be used as the predictor for poor prognosis, which might be caused by the potential chemoradiation resistance of the cervical cancer patients. The mechanism deserves further exploration. Funding. This study was supported by Science Foundation for Young Scholars of Fudan University. The authors declared no conflicts of interest. AOSP25 EXPRESSION OF SURVIVIN, FAS, CYCLIN E, AND CASPASE-3 IN APOPTOTIC BREAST CANCER CELLS INDUCED BY ELECTROCHEMICAL THERAPY B. Zhoua, C. Weib, Z. Zhangb, T. Yangb, S. Yua, J. Yua, W. Looc *, L. Chowc, A. Yipc. aNingxia People’s Hospital, Yinchuan, China, bNingxia Medical University, Yinchuan, China, cOrganisation for Oncology and Translational Research and UNIMED Medical Institute, Hong Kong Introduction. Electrochemical therapy (EChT) in malignant tumours had been identified as a possible adjunctive treatment for cancers. However, the mechanism of action remains largely unknown. In this study, we explored further the mechanisms of EChT on breast cancer cell line in vitro by detecting cell growth, cell cycle changes, cell apoptosis, and protein expression of survivin, Fas, cyclin E, and caspase-3. Methods.Humanbreast cancer cellswere treated by EChTwith different levels of electricity at 0C (control), 3C, 5C, 10C, and 20C. Cell inhibition, cell cycle distribution, and cell apoptosis were analysed by MMT and flow cytometry analysis. The expression of survivin, Fas, cyclin E, and caspase-3 in breast cancer cells was analysed with western blot. Results.The cell inhibitory rate and necrosis were significantly increased in breast cancer cells after EChT treatment compared with control (p<0.05). The apoptosis ratio within 3C, 5C, and 10C was increased obviously in order. The proportion of G0/G1 phase was higher than that in control group (p<0.05). The expression levels of survivin, cyclin E, and caspase-3 protein in the treatment group were decreased, but the expression of Fas protein was increased with higher power of EChT treatment. Discussion. The study showed that EChT could inhibit breast cancer cell growth by regulating apoptotic pathway proteins such as survivin, Fas, and cyclin E, and arresting the cell cycle at G0/G1 phase. Considering the change in expression of the regulatory proteins and strong apoptotic effect of EChT in breast cancer cells, further investigation is warranted to explore its possible treatment strategy in breast cancer. Funding. This study was supported by Natural Science grant of Ningxia, China (NZ009164). The authors declared no conflicts of interest. AOSP26 EFFECT OF RAT HYPERPLASIA SUPPRESSOR GENE ON GLIOMA IN VIVO AND IN VITRO P. Gaoa, Y. Zoua, Z. Wangc, W. Haod, H. Guoa, B. Zhanga, W. Zhaob, B. Shena *. aThe General Hospital of Ningxia Medical University, Yinchuan, China, bNingxia Medical University, Yinchuan, China, cThe Zhengzhou No. 7 People’s Hospital, Zhengzhou, China, dThe Affiliated Hospital of Yanan University,

AOSP22 USE OF PROPHYLACTIC GASTROSTOMY TUBE BEFORE CHEMORADIATION IN LOCALLY ADVANCED HEAD AND NECK CANCER PATIENTS

s, 5th AOS and 9th Annual Conference of OOTR, 2013 / European Journal of Cancer 49S1 (2013) S1−S22 S15 Discussion. Polz expression can be used as the predictor for poor prognosis, which might be caused by the potential chemoradiation resistance of the cervical cancer patients. The mechanism deserves further exploration. Funding. This study was supported by Science Foundation for Young Scholars of Fudan University. The authors declared no conflicts of interest. AOSP25 EXPRESSION OF SURVIVIN, FAS, CYCLIN E, AND CASPASE-3 IN APOPTOTIC BREAST CANCER CELLS INDUCED BY ELECTROCHEMICAL THERAPY B. Zhoua, C. Weib, Z. Zhangb, T. Yangb, S. Yua, J. Yua, W. Looc *, L. Chowc, A. Yipc. aNingxia People’s Hospital, Yinchuan, China, bNingxia Medical University, Yinchuan, China, cOrganisation for Oncology and Translational Research and UNIMED Medical Institute, Hong Kong Introduction. Electrochemical therapy (EChT) in malignant tumours had been identified as a possible adjunctive treatment for cancers. However, the mechanism of action remains largely unknown. In this study, we explored further the mechanisms of EChT on breast cancer cell line in vitro by detecting cell growth, cell cycle changes, cell apoptosis, and protein expression of survivin, Fas, cyclin E, and caspase-3. Methods.Humanbreast cancer cellswere treated by EChTwith different levels of electricity at 0C (control), 3C, 5C, 10C, and 20C. Cell inhibition, cell cycle distribution, and cell apoptosis were analysed by MMT and flow cytometry analysis. The expression of survivin, Fas, cyclin E, and caspase-3 in breast cancer cells was analysed with western blot. Results.The cell inhibitory rate and necrosis were significantly increased in breast cancer cells after EChT treatment compared with control (p<0.05). The apoptosis ratio within 3C, 5C, and 10C was increased obviously in order. The proportion of G0/G1 phase was higher than that in control group (p<0.05). The expression levels of survivin, cyclin E, and caspase-3 protein in the treatment group were decreased, but the expression of Fas protein was increased with higher power of EChT treatment. Discussion. The study showed that EChT could inhibit breast cancer cell growth by regulating apoptotic pathway proteins such as survivin, Fas, and cyclin E, and arresting the cell cycle at G0/G1 phase. Considering the change in expression of the regulatory proteins and strong apoptotic effect of EChT in breast cancer cells, further investigation is warranted to explore its possible treatment strategy in breast cancer. Funding. This study was supported by Natural Science grant of Ningxia, China (NZ009164). The authors declared no conflicts of interest. AOSP26 EFFECT OF RAT HYPERPLASIA SUPPRESSOR GENE ON GLIOMA IN VIVO AND IN VITRO P. Gaoa, Y. Zoua, Z. Wangc, W. Haod, H. Guoa, B. Zhanga, W. Zhaob, B. Shena *. aThe General Hospital of Ningxia Medical University, Yinchuan, China, bNingxia Medical University, Yinchuan, China, cThe Zhengzhou No. 7 People’s Hospital, Zhengzhou, China, dThe Affiliated Hospital of Yanan University,

AOSP26 EFFECT OF RAT HYPERPLASIA SUPPRESSOR GENE ON GLIOMA IN VIVO AND IN VITRO

s, 5th AOS and 9th Annual Conference of OOTR, 2013 / European Journal of Cancer 49S1 (2013) S1−S22 S15 Discussion. Polz expression can be used as the predictor for poor prognosis, which might be caused by the potential chemoradiation resistance of the cervical cancer patients. The mechanism deserves further exploration. Funding. This study was supported by Science Foundation for Young Scholars of Fudan University. The authors declared no conflicts of interest. AOSP25 EXPRESSION OF SURVIVIN, FAS, CYCLIN E, AND CASPASE-3 IN APOPTOTIC BREAST CANCER CELLS INDUCED BY ELECTROCHEMICAL THERAPY B. Zhoua, C. Weib, Z. Zhangb, T. Yangb, S. Yua, J. Yua, W. Looc *, L. Chowc, A. Yipc. aNingxia People’s Hospital, Yinchuan, China, bNingxia Medical University, Yinchuan, China, cOrganisation for Oncology and Translational Research and UNIMED Medical Institute, Hong Kong Introduction. Electrochemical therapy (EChT) in malignant tumours had been identified as a possible adjunctive treatment for cancers. However, the mechanism of action remains largely unknown. In this study, we explored further the mechanisms of EChT on breast cancer cell line in vitro by detecting cell growth, cell cycle changes, cell apoptosis, and protein expression of survivin, Fas, cyclin E, and caspase-3. Methods.Humanbreast cancer cellswere treated by EChTwith different levels of electricity at 0C (control), 3C, 5C, 10C, and 20C. Cell inhibition, cell cycle distribution, and cell apoptosis were analysed by MMT and flow cytometry analysis. The expression of survivin, Fas, cyclin E, and caspase-3 in breast cancer cells was analysed with western blot. Results.The cell inhibitory rate and necrosis were significantly increased in breast cancer cells after EChT treatment compared with control (p<0.05). The apoptosis ratio within 3C, 5C, and 10C was increased obviously in order. The proportion of G0/G1 phase was higher than that in control group (p<0.05). The expression levels of survivin, cyclin E, and caspase-3 protein in the treatment group were decreased, but the expression of Fas protein was increased with higher power of EChT treatment. Discussion. The study showed that EChT could inhibit breast cancer cell growth by regulating apoptotic pathway proteins such as survivin, Fas, and cyclin E, and arresting the cell cycle at G0/G1 phase. Considering the change in expression of the regulatory proteins and strong apoptotic effect of EChT in breast cancer cells, further investigation is warranted to explore its possible treatment strategy in breast cancer. Funding. This study was supported by Natural Science grant of Ningxia, China (NZ009164). The authors declared no conflicts of interest. AOSP26 EFFECT OF RAT HYPERPLASIA SUPPRESSOR GENE ON GLIOMA IN VIVO AND IN VITRO P. Gaoa, Y. Zoua, Z. Wangc, W. Haod, H. Guoa, B. Zhanga, W. Zhaob, B. Shena *. aThe General Hospital of Ningxia Medical University, Yinchuan, China, bNingxia Medical University, Yinchuan, China, cThe Zhengzhou No. 7 People’s Hospital, Zhengzhou, China, dThe Affiliated Hospital of Yanan University,

Targeting Survivin’s Co-Conspirators: Do Alternative Methods of Trapping Survivin in the Nucleus Have Potential in Triple-Negative Breast Cancer Therapy?

Future OncologyVol. 8, No. 8 EditorialTargeting survivin’s co-conspirators: do alternative methods of trapping survivin in the nucleus have potential in triple-negative breast cancer therapy?Michael P Holloway & Rachel A AlturaMichael P HollowayThe Warren Alpert Medical School at Brown University & Rhode Island Hospital, Providence, RI, USASearch for more papers by this author & Rachel A Altura* Author for correspondenceDepartment of Pediatrics, The Warren Alpert Medical School at Brown University & Rhode Island Hospital, 593 Eddy Street, MPS 126, Providence, RI 02903, USA. Search for more papers by this authorEmail the corresponding author at rachel_altura@brown.eduPublished Online:15 Aug 2012https://doi.org/10.2217/fon.12.77AboutSectionsView ArticleView Full TextPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit View articleKeywords: breast cancerCRM1HDAC6survivinReferences1 Foulkes WD, Smith IE, Reis-Filho JS. Triple-negative breast cancer. N. Engl. J. Med.363(20),1938–1948 (2010).Crossref, Medline, CAS, Google Scholar2 Badve S, Dabbs DJ, Schnitt SJ et al. Basal-like and triple-negative breast cancers: a critical review with an emphasis on the implications for pathologists and oncologists. Mod. Pathol.24(2),157–167 (2011).Crossref, Medline, Google Scholar3 Altieri DC. Survivin, cancer networks and pathway-directed drug discovery. Nat. Rev. Cancer8(1),61–70 (2008).Crossref, Medline, CAS, Google Scholar4 Colnaghi R, Connell CM, Barrett RM, Wheatley SP. 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Nuclear or cytoplasmic expression of survivin: what is the significance? Int. J. Cancer114(4),509–512 (2005).Crossref, Medline, CAS, Google Scholar10 Chan KS, Wong CH, Huang YF, Li HY. Survivin withdrawal by nuclear export failure as a physiological switch to commit cells to apoptosis. Cell Death Dis.1,e57 (2010).Crossref, Medline, Google Scholar11 Tanaka K, Iwamoto S, Gon G, Nohara T, Iwamoto M, Tanigawa N. Expression of survivin and its relationship to loss of apoptosis in breast carcinomas. Clin. Cancer Res.6(1),127–134 (2000).Medline, CAS, Google Scholar12 Sohn DM, Kim SY, Baek MJ et al. Expression of survivin and clinical correlation in patients with breast cancer. Biomed. Pharmacother.60(6),289–292 (2006).Crossref, Medline, CAS, Google Scholar13 Kennedy SM, O’Driscoll L, Purcell R et al. Prognostic importance of survivin in breast cancer. Br. J. Cancer88(7),1077–1083 (2003).Crossref, Medline, CAS, Google Scholar14 Knauer SK, Bier C, Habtemichael N, Stauber RH. The survivin–Crm1 interaction is essential for chromosomal passenger complex localization and function. EMBO Rep.7(12),1259–1265 (2006).Crossref, Medline, CAS, Google Scholar15 Engelsma D, Rodriguez JA, Fish A, Giaccone G, Fornerod M. Homodimerization antagonizes nuclear export of survivin. Traffic8(11),1495–1502 (2007).Crossref, Medline, CAS, Google Scholar16 Wang H, Holloway MP, Ma L et al. Acetylation directs survivin nuclear localization to repress STAT3 oncogenic activity. J. Biol. Chem.285(46),36129–36137 (2010).Crossref, Medline, CAS, Google Scholar17 Riolo MT, Cooper ZA, Holloway MP et al. HDAC6 deacetylates survivin for its nuclear export in breast cancer. J. Biol. Chem.287(14),10885–10893 (2012).Crossref, Medline, CAS, Google Scholar18 Yakirevich E, Samkari A, Holloway MP et al. Total survivin and acetylated survivin correlate with distinct molecular subtypes of breast cancer. Hum. 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Drugs19(9),1049–1066 (2010).Crossref, Medline, CAS, Google ScholarFiguresReferencesRelatedDetailsCited ByTargeting Survivin in Cancer: Novel Drug Development Approaches18 August 2013 | BioDrugs, Vol. 28, No. 1Association of survivin splice variants with prognosis and treatment of breast cancerWorld Journal of Clinical Oncology, Vol. 5, No. 5 Vol. 8, No. 8 eToC Sign up Follow us on social media for the latest updates Metrics Downloaded 208 times History Published online 15 August 2012 Published in print August 2012 Information© Future Medicine LtdKeywordsbreast cancerCRM1HDAC6survivinFinancial & competing interests disclosureFunding for the work described here was supported by the National Institute of General Medical Sciences of the NIH under award number P20GM103421. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.PDF download

Targeting survivin in cancer

With almost 4000 citations in Medline in a little over 10years, survivin has certainly kept scores of investigators busy worldwide. Tangible progress has been made in revealing the multiple functions of survivin, uncovering their wirings as integrated cellular networks, and mapping their exploitation in virtually every human tumor, in vivo. Considering the normally long and excruciating timeline of oncology drug discovery, it is clearly a resounding success that a better understanding of survivin biology has led to several clinical trials of survivin-based therapeutics in cancer patients. However, the portfolio of survivin antagonists available in the clinic remains small, pressing the need for a less rigid drug development approach to fully unlock the potential of this unique, albeit unconventional oncology drug target.

Locked Nucleic Acids Technology for Targeting Survivin in Cancer and Viral Infections

*Corresponding author: Dr. Jagat R. Kanwar, Associate Professor of Immunology and Cell Biology, Nanomedicine-Laboratory of Immunology and Molecular Biomedical Research (NLIMBR), Institute for Frontier Materials (IFM), Deakin University, Geelong, Geelong Technology Precinct (GTP), Deakin University, Pigdons Road, Waurn Ponds, Geelong, Victoria 3217, Australia, Tel: 0061-3-52271148; Fax: 0061-3-5227-3402; E-mail: jagat.kanwar@deakin.edu.au

Survivin in Cancer: A Spider in the Web

Survivin in Cancer: A Spider in the Web

The regulation of antitumor immune responses by helper T cells—From the bench research to the discovery of H/K-HELP cancer vaccine—

During past decades, cancer vaccine therapy has been focused on only the activation of CTL, but its therapeutic effect was not successful though long SD was induced. The failure of cancer vaccine is derived from (i) the existence of a strong tumor escape mechanisms and (ii) the ignorance of helper T cell activation. We have proposed that Th1-dominant immunity played a critical role for overcoming immunosuppressive tumor-escape mechanisms to induce tumor-specific CTL, which are essential for the complete cure of tumor and prevention of tumor recurrence. To apply these basic findings, we started a clinical trial of a novel cancer vaccine/cell therapy (Th1 cell therapy) using H/K-HELP of MAGE-A4 or Survivin cancer antigen. In phase I study, H/K-HELP consisted of both killer and helper epitopes and Th1 adjuvants (OK-432 and Montanide) were subcutaneously administered into cancer patients 4 times at 2 wks intervals. Both MAGE-A4-H/K-HELP and Survivin-H/K-HELP cancer vaccine induced cancer-specific Th1 and Tc1 immune responses and cancer-specific C-fixing antibodies (IgG1 and IgG3) in cancer patients. Moreover, Survivin-H/K-HELP vaccination induced a complete regression of chemo and radio-resistant lateral deep cervical node recurrence of triple-negative breast cancer. H/K-HELP vaccination with Th1 adjuvants or its combination with Th1 cells will become a promising cancer vaccine/cell therapy of human cancer.

The study on the induction of specific immune cytotoxic T lymphocyte responses against pancreatic cancer by transfected dendritic cells with common tumor antigen survivin mRNAs in vitro

Objective To investigate the induction of specific anti-tumor immune response by transfected dendritic cells (DCs) with survivin mRNA of human pancreatic cancer, and to provide the experimental evidences for the treatment of human pancreatic cancer with DCs vaccine. Methods DCs were isolated and cultured from peripheral blood mononuclear cells (PBMCs). After being transcripted and amplified, survivin mRNA was transfected into DCs by electroporation. The expression of survivin in DCs at different time points was detected by quantitative real-time PCR. The survival rate of DCs before and after transfection was determined by MTT method. The induction of specific cytotoxic T lymphocyte (CTL) response by survivin mRNA transfected DCs was measured by 51Cr standard cytotoxicity test. The induction of specific CTL activation by survivin mRNA transfected DCs was evaluated through testing released IFN-γ by ELISA method. Results After survivin mRNA transfection for 48h, the expression of survivin mRNA in DCs reached the highest point (46.09±6.57). After transfection, the survival rate of DCs was stabilized around 80%. The DCs transfected with survivin mRNA could effectively induce HLA-A2+ / survivin+ specific CTL immune responses. Stimulated with pancreatic cancer cell line Capan-2 cells or SCL-1 cells as control group, the IFN-γ released in 24 hours by survivin specific CTL were (28.79±5.70) U/ml and (25.12±2.13) U/ml respectively, there was no significant difference (P=0.761). Conclusion The induction of CTLs by DCs transfected with human pancreatic cancer survivin mRNA could produce specific anti-tumor immunity. Key words: Dendritic cells; Microtubule-associated proteins; RNA, messenger; Transfection; Pancreatic neoplasms; T-lymphocytes, cytotoxic