Browsing by Subject "Survivin"

Now showing 1 - 4 of 4
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    A novel survivin dimerization inhibitor without a labile hydrazone linker induces spontaneous apoptosis and synergizes with docetaxel in prostate cancer cells
    (Elsevier, 2022) Peery, Robert; Cui, Qingbin; Kyei-Baffour, Kwaku; Josephraj, Sophia; Huang, Caoqinglong; Dong, Zizheng; Dai, Mingji; Zhang, Jian-Ting; Liu, Jing-Yuan; Pharmacology and Toxicology, School of Medicine
    Survivin, a member of the inhibitor of apoptosis protein family, exists as a homodimer and is aberrantly upregulated in a wide spectrum of cancers. It was thought to be an ideal target due to its lack of expression in most adult normal tissues and importance in cancer cell survival. However, it has been challenging to target survivin due to its "undruggable" nature. We previously attempted to target its dimerization domain with a hypothesis that inhibiting survivin dimerization would promote its degradation in proteasome, which led to identification of a lead small-molecule inhibitor, LQZ-7F. LQZ-7F consists of a flat tetracyclic aromatic core with labile hydrazone linking a 1,2,5-oxadiazole moiety. In this study, we tested the hypothesis that LQZ-7F could be developed as a prodrug because the labile hydrazone linker could be hydrolyzed, releasing the tetracyclic aromatic core. To this end, we synthesized the tetracyclic aromatic core (LQZ-7F1) using reported procedure and tested LQZ-7F1 for its biological activities. Here we show that LQZ-7F1 has a significantly improved potency with submicromolar IC50's and induces spontaneous apoptosis in prostate cancer cells. It also more effectively inhibits survivin dimerization and induces survivin degradation in a proteasome-dependent manner than LQZ-7F. We also show that the combination of LQZ-7F1 and docetaxel have strong synergism in inhibiting prostate cancer cell survival. Together, we conclude that the hydrazone linker with the oxadiazole tail is dispensable for survivin inhibition and the survivin dimerization inhibitor, LQZ-7F, may be developed as a prodrug for prostate cancer treatment and to overcome docetaxel resistance.
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    The role of inhibitor of apoptosis (IAP) family member survivin in prostatic disease
    (2017-06-23) McIlwain, David W.; Lu, Tao; Fishel, Melissa L.; Jerde, Travis J.; Mosley, Amber L.; Zhang, Jian-ting
    Continual and recalcitrant inflammation is an extremely common condition in the human prostate and has been found to be associated with a number of prostatic diseases including prostate cancer and benign prostatic hyperplasia (BPH). While much has been described regarding prostate disease resulting from oxygen and nitrogen radicals during inflammation, proliferative mechanisms associated with repair and regeneration are less understood. The Inhibitor of Apoptosis (IAP) family member survivin has been found to be overexpressed during inflammation and associated with prostate cancer progression. Apurinic/apyrimidinic endonuclease 1/redox effector factor 1 (APE1/Ref-1) is a multifunctional protein that is essential in activating inflammatory transcription factors. Because APE1/Ref-1 is expressed and elevated in prostate cancer, we sought to characterize APE1/Ref-1 expression and activity in human prostate cancer cell lines and determine the effect of selective reduction-oxidation (redox) function inhibition on prostate cancer cells in vitro and in vivo. Due to the role of inflammatory transcriptional activators NFĸB and STAT3 in survivin protein expression, and APE1/Ref-1 redox activity regulating their transcriptional activity, we assessed selective inhibition of APE1/Ref-1’s redox function as a novel method to halt prostate cancer cell growth and survival. Our study demonstrates that survivin and APE1/Ref-1 are significantly higher in human prostate cancer specimens compared to noncancerous controls and that APE1/Ref-1 redox specific inhibition with small molecule inhibitors APX3330 and APX2009 decreases prostate cancer cell proliferation and induces cell cycle arrest. Inhibition of APE1/Ref-1 redox function significantly reduced NFĸB transcriptional activity, survivin mRNA and survivin protein levels. These data indicate that APE1/Ref-1 is a key regulator of survivin and a potentially viable target in prostate cancer.
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    The roles of prostate progenitor cells and survivin in inflammation-induced prostate epithelial hyperplasia
    (2016-09-06) Wang, Liang; Jerde, Travis; Safa, Ahmad; Srour, Edward F.; Zhang, Jian-ting; Lu, Tao
    Prostate inflammation is a common health concern as an important risk factor for prostate cancer and Benign Prostatic Hyperplasia (BPH). Inflammation induces epithelial apoptosis and epithelial hyperplasia, suggesting that inflammation promotes the tissue repair and regeneration process. Progenitor cells are critical in maintaining epithelial homeostasis in adult tissues. However, the roles of prostate progenitor cells, especially during prostate inflammation, are understudied. I proposed that prostate epithelial progenitor cells (PEPCs) are involved in inflammation-induced epithelial hyperplasia, and are driven by regulation from inflammatory pathways. Here, we showed that sphere formation ability of prostate epithelial cells is increased by inflammation. We identified that a population of prostate progenitor cells, named prostate epithelial progenitor cells, were expanded by inflammation under the regulation of IL-1/insulin-like growth factor 1 (IGF-1) signaling pathway, a previously identified critical regulation pathway of inflammation-induced epithelial hyperplasia. The expansion of PEPCs also correlated with the intensity of inflammation. We then identified that survivin was upregulated in prostate epithelial cells by inflammation and was mainly co-localized with proliferation markers in prostate epithelial cells. This upregulation depended on IL-1/IGF-1 signaling. In vivo treatment with the survivin inhibitor LQZ-7F reduced both survivin expression and proliferation in prostate epithelial cells during inflammation. Using our label retaining strategy, we compared the survivin expression pattern in two prostate regeneration models. We discovered that different populations of progenitor cells may be involved in different regeneration processes. We identified that survivin was expressed in a specific population of reactivated cells that respond to the inflammatory environment and was independent of the known slow-cycling stem cells found in the prostate epithelium. In summary, I have identified that PEPCs are involved in epithelial hyperplasia and are dependent on survivin signaling. My work defines how survivin serves as a key regulator of epithelial hyperplasia in an inflammatory environment.
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    Survivin is Required for Mouse and Human Bone Marrow Mesenchymal Stromal Cell Function
    (Wiley, 2017) Singh, Pratibha; Fukuda, Seiji; Liu, Liqiong; Chitteti, Brahmananda Reddy; Pelus, Louis M.; Microbiology and Immunology, School of Medicine
    Although mesenchymal stromal cells (MSCs) have significant potential in cell-based therapies, little is known about the factors that regulate their functions. While exploring regulatory molecules potentially involved in MSC activities, we found that the endogenous multifunctional factor Survivin is essential for MSC survival, expansion, lineage commitment, and migration. Pharmacological or genetic blockade of Survivin expression in mouse and human bone marrow MSC enhances caspase 3 and 7 expression and reduces proliferation resulting in fewer MSC and clonogenic colony-forming unit-fibroblasts (CFU-F), whereas ectopic Survivin overexpression in MSC results in their expansion. Survivin is also required for the MSC proliferative responses to basic fibroblast growth factor and platelet derived growth factor. In a wound healing model, Survivin inhibition results in suppression of MSC migration to the wound site. In addition, loss of Survivin in MSCs compromises their hematopoiesis-supporting capacity. These results demonstrate that Survivin is a key regulator of mouse and human MSC function, and suggest that targeted modulation of Survivin in MSCs may have clinical utility to enhance MSC recovery and activity following insult or stress.