Survivin as a prognostic/predictive marker and molecular target in cancer therapy.
ABSTRACT Evasion from apoptotic cell death is reported to be a pivotal mechanism by which tumor cells acquire resistance to therapeutic treatment. Targeting the apoptotic pathways may constitute a promising strategy to counteract therapy resistance and to re-sensitize cancer cells. Expression of survivin, the smallest and structurally unique member of the inhibitor of apoptosis protein (IAP) family, has been shown to be associated with poor clinical outcome, more aggressive clinicopathologic features and resistance to both, conventional chemo and radiation therapy. Moreover, survivin detection in cancer tissue, in circulating tumor cells and in patient's serum has prognostic and predictive relevance and may display a prerequisite for marker based molecular therapies. Indeed, due to its universal over expression in malignant tissue, and its prominent role at disparate networks of cellular division, intracellular signaling, apoptosis and adaption to unfavorable surroundings, survivin has been shown to be a suitable target for a targeted therapy. The applicability of survivindriven strategies in clinical practice is currently under investigation as the first survivin antagonists (small molecule inhibitors, antisense oligonucleotides and immunotherapy) successfully entered phase I/II trials. Taken together, these data provide a rationale for the implementation of both, survivin as a molecular diagnostic tool and survivin targeted therapies, within future clinical practice.
SourceAvailable from: Mei-Chen Yang[Show abstract] [Hide abstract]
ABSTRACT: Survivin, a structurally unique protein expressed in most common human neoplasms, is thought to support cell cycle progression and suppress apoptosis. Survivin expression is highly correlated with advanced non-small cell lung cancer (NSCLC) and poor prognosis. In this retrospective study of banked pathology tissue of patients with advanced NSCLC, we tested for correlations of N-survivin expression in tumor tissues and responsiveness to treatment with platinum-based regimens containing paclitaxel or docetaxel. The 48 patients with NSCLC included 32 (66.7 %) males and 16 (33.3 %) females. Mean age at diagnosis was 59.4 years (range 36-83 years), and median follow-up time was 20.4 months (range 3.4-59.0 months). Patients with high tumor N-survivin expression had significantly better responses to taxane-platinum chemotherapy than those with low tumor N-survivin expression (P < 0.001). Adjusted multivariate modeling found high tumor N-survivin expression to be an independent prognostic factor for a clinical response to chemotherapy (high vs. low, OR 6.14, 95 % CI 1.62-23.29; P = 0.008). Median overall survival differed significantly between those with high tumor N-survivin expression who did/did not respond to chemotherapy and between those with low tumor N-survivin expression who did/did not respond to chemotherapy (P < 0.05). Tumor N-survivin expression shows promise as a predictive biomarker in the chemotherapy setting as a surrogate marker of high proliferation status.Medical Oncology 08/2014; 31(8):79. DOI:10.1007/s12032-014-0079-4 · 2.06 Impact Factor
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ABSTRACT: Background CCN1 plays distinct roles in various tumor types, but little is known regarding the role of CCN1 in leukemia. Methods We analyzed CCN1 protein expression in leukemia cell lines and in AML bone marrow samples. We also evaluated the effects of antibody- or siRNA-mediated inhibition of CCN1 on the growth of two AML cell lines (U937 and Kasumi-1 cells) and on the MEK/ERK pathway, β-catenin and other related genes. Results U937 and Kasumi-1 cells had markedly higher CCN1 expression than the 5 other leukemia cell lines, and CCN1 protein expression was higher in the AML bone marrow samples than in the normal bone marrow samples. Blocking CCN1 with an antibody in U937 and Kasumi-1 cells suppressed proliferation, increased apoptosis, down-regulated Bcl-xL and c-Myc expression, up-regulated Bax expression, and had no effect on Survivin. siRNA-mediated down-regulation of CCN1 inhibited the proliferation and colony formation of U937 and Kasumi-1 cells and increased cytarabine-induced apoptosis. Furthermore, CCN1 siRNA reduced MEK and ERK phosphorylation without affecting β-catenin; the CCN1 antibody similarly affected MEK and ERK phosphorylation. These changes in phosphorylation could influence the expression of Bcl-xL, c-Myc and Bax in AML cells. Conclusions The data suggested that CCN1 is a tumor promoter in AML that acts through the MEK/ERK pathway to up-regulate c-Myc and Bcl-xL and to down-regulate Bax.Cancer Cell International 08/2014; 14:74. DOI:10.1186/s12935-014-0074-z · 1.99 Impact Factor
Article: SURVIVIN–THE INCONVENIENT IAP[Show abstract] [Hide abstract]
ABSTRACT: Although technically a member of the Inhibitor of Apoptosis (IAP) gene family, survivin has consistently defied assumptions, refuted predictions and challenged paradigms. Despite its more than 5,500 citations currently in Medline, the biology of survivin has remained fascinatingly complex, its exploitation in human disease, most notably cancer, tantalizing, and its regulation of cellular homeostasis unexpectedly far-reaching. An inconvenient outsider that resists schemes and dogmas, survivin continues to hold great promise to unlock fundamental circuitries of cellular functions in health and disease.Seminars in Cell and Developmental Biology 01/2015; DOI:10.1016/j.semcdb.2014.12.007 · 5.97 Impact Factor