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

Abstract

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.

siRNA-mediated Silencing of Survivin Inhibits Proliferation and Enhances Etoposide Chemosensitivity in Acute Myeloid Leukemia Cells

“…Furthermore, survivin is required for stabilization of spindle microtubules and accurate chromosome segregation during mitosis. However, the exact roles of survivin in regulation of cell division and apoptosis are still unclear (Zaffaroni and Daidone, 2002;Zaffaroni et al, 2005;Kelly et al, 2011;Church and Talbot, 2012).…”

HNF1b is involved in prostate cancer risk via modulating androgenic hormone effects and coordination with other genes

“…The overexpression of HSPD1 may be potentially associated with the progression and prognosis of prostate cancer (Cornford et al, 2000). HSPD1 could suppress tumor cell apoptosis by maintaining stability of mitochondria (Ghosh et al, 2010), restraining p53 and enhancing a common cancer gene called survivin (Ghosh et al, 2008;Kelly et al, 2011). HSPD1 has also been demonstrated to be associated with early onset of hormone refractory disease in advanced prostate cancer patients under androgen ablation therapy (Castilla et al, 2010).…”

Transcriptional upregulation of HNF-1β by NF-κB in ovarian clear cell carcinoma modulates susceptibility to apoptosis through alteration in bcl-2 expression

“…In general, ovarian carcinomas accompanied by endometriosis show relatively higher level of 8-hydroxy-2′-deoxyguanosine (8-OHdG), which indicates severe oxidative DNA damage, 15 in line with our results demonstrating that pp65 scores were significantly higher in OCCCs as compared with the other subtypes of ovarian carcinomas. Given that the extrinsic apoptotic pathway is activated by cell death receptors, such as TNF-α receptors, 30,31 it is suggested that both extrinsic and intrinsic apoptotic pathways may be activated in OCCCs. With regard to overexpression of exogenous HNF-1β by treatment of the stable cells with doxorubicin, it appeared that toxic insults may also contribute to the regulation.…”