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International Journal of Biological... 2024Nasopharyngeal carcinoma (NPC) is the most common cancer originating in the nasopharynx. Despite continuous improvement in treatment strategies, recurrence or...
Nasopharyngeal carcinoma (NPC) is the most common cancer originating in the nasopharynx. Despite continuous improvement in treatment strategies, recurrence or persistence of cancer after radiotherapy is still inevitable, highlighting the need to identify therapeutic resistance factors and develop effective methods for NPC treatment. Herein, we found that TRAF4 is overexpressed in NPC cells and tissues. Knockdown TRAF4 significantly increased the radiosensitivity of NPC cells, possibly by inhibiting the Akt/Wee1/CDK1 axis, thereby suppressing survivin phosphorylation and promoting its degradation by FBXL7. TRAF4 is positively correlated with p-Akt and survivin in NPC tissues. High protein levels of TRAF4 were observed in acquired radioresistant NPC cells, and knockdown of TRAF4 overcomes radioresistant and the xenograft mouse model. Altogether, our study highlights the TRAF4-survivin axis as a potential therapeutic target for radiosensitization in NPC.
Topics: Humans; Animals; Mice; Carcinoma; Nasopharyngeal Neoplasms; Proto-Oncogene Proteins c-akt; Survivin; TNF Receptor-Associated Factor 4; Signal Transduction; Nasopharyngeal Carcinoma; Ubiquitination
PubMed: 38164179
DOI: 10.7150/ijbs.87180 -
BioDrugs : Clinical Immunotherapeutics,... Feb 2014Survivin is a well-established target in experimental cancer therapy. The molecule is over-expressed in most human tumors, but hardly detectable in normal tissues.... (Review)
Review
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.
Topics: Drug Design; Humans; Inhibitor of Apoptosis Proteins; Ligands; Molecular Targeted Therapy; Molecular Weight; Neoplasms; Peptides; Small Molecule Libraries; Survivin
PubMed: 23955284
DOI: 10.1007/s40259-013-0058-x -
Cancer Letters May 2013With almost 4000 citations in Medline in a little over 10 years, survivin has certainly kept scores of investigators busy worldwide. Tangible progress has been made in... (Review)
Review
With almost 4000 citations in Medline in a little over 10 years, 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.
Topics: Animals; Chemistry, Pharmaceutical; Clinical Trials as Topic; Drug Delivery Systems; Drug Design; Gene Expression Regulation, Neoplastic; Humans; Immunotherapy; Inhibitor of Apoptosis Proteins; Microtubule-Associated Proteins; Neoplasm Proteins; Neoplasms; Oligonucleotides, Antisense; Signal Transduction; Survivin
PubMed: 22410464
DOI: 10.1016/j.canlet.2012.03.005 -
Journal of Experimental & Clinical... Mar 2021Dedifferentiated liposarcoma (DDLPS), a tumor that lacks effective treatment strategies and is associated with poor outcomes, expresses amplified MDM2 in the presence of...
Selinexor versus doxorubicin in dedifferentiated liposarcoma PDXs: evidence of greater activity and apoptotic response dependent on p53 nuclear accumulation and survivin down-regulation.
BACKGROUND
Dedifferentiated liposarcoma (DDLPS), a tumor that lacks effective treatment strategies and is associated with poor outcomes, expresses amplified MDM2 in the presence of wild-type p53. MDM2 ubiquitination of p53 facilitates its XPO1-mediated nuclear export, thus limiting p53 tumor suppressor functions. Consequently, nuclear export is a rational target in DDLPS. We directly compared the antitumor activity of the first-in class XPO1 inhibitor selinexor and doxorubicin, the standard front-line therapy in sarcomas, in DDLPS patient-derived xenografts (PDXs) and primary cell lines.
METHODS
Drug activity was assessed in three PDXs (and two corresponding cell lines) established from the dedifferentiated component of primary untreated retroperitoneal DDLPS with myogenic (N = 2) and rhabdomyoblastic (N = 1) differentiation from patients who underwent surgery. These models were marked by amplification of MDM2, CDK4 and HMGA2 genes.
RESULTS
Selinexor was moderately active in the three PDXs but achieved greater tumor response compared to doxorubicin (maximum tumor volume inhibition: 46-80 % vs. 37-60 %). The PDX harboring rhabdomyoblastic dedifferentiation showed the highest sensitivity to both agents. PDX response to selinexor and doxorubicin was not associated with the extent of MDM2 and CDK4 gene amplification. Interestingly, the most chemosensitive PDX model showed the lowest extent of HMGA2 amplification. Selinexor was also more efficient than doxorubicinin in inducing an apoptotic response in PDXs and cell lines. Consistently, an increased nuclear accumulation of p53 was seen in all selinexor-treated models. In addition, a time-dependent decrease of survivin expression, with an almost complete abrogation of the cytoplasmic anti-apoptotic pool of this protein, was observed as a consequence of the decreased acetylation/activation of STAT3 and the increased ubiquitination of nuclear survivin.
CONCLUSIONS
Selinexor showed a moderate antitumor activity in three DDLPS PDXs, which was, however, consistently higher than doxorubicin across all different models regardless the extent of MDM2 amplification and the histological differentiation. The depletion of survivin protein seems to significantly contribute to the induction of apoptosis through which selinexor exerts its antitumor activity.
Topics: Animals; Antibiotics, Antineoplastic; Apoptosis; Cell Dedifferentiation; Cell Nucleus; Down-Regulation; Doxorubicin; Humans; Hydrazines; Liposarcoma; Male; Mice; Mice, Nude; Random Allocation; Survivin; Triazoles; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays
PubMed: 33648535
DOI: 10.1186/s13046-021-01886-x -
Molecular Metabolism Apr 2022Survivin is a member of the inhibitor of apoptosis family. Our previous study showed that survivin expression could be strongly induced by long-term, high-fat diet (HFD)...
OBJECTIVE
Survivin is a member of the inhibitor of apoptosis family. Our previous study showed that survivin expression could be strongly induced by long-term, high-fat diet (HFD) exposure in vivo. It could also be induced by insulin through the PI3K/mTOR signaling pathway in vitro. Therefore, we hypothesized that under certain conditions, survivin expression might be required for adipocyte function. In the current study, we aim to further investigate the regulation of survivin expression in mature adipocytes upon various nutritional stimuli and the role of survivin using adipocyte-specific survivin knockout (SKO) mice.
METHODS
SKO mice were obtained by crossing survivin mice with Adiponectin-Cre mice. The overall metabolic phenotype was observed under chow diet (CD) and HFD feeding conditions. The thermogenic program of mice was detected upon cold exposure. The inguinal white adipose tissue (iWAT) and brown adipose tissue (BAT) stromal vascular fraction cells were isolated and differentiated into mature adipocytes, and the effects of survivin deletion on mature adipocyte function were detected in vitro.
RESULTS
Survivin expression in adipose tissue and adipocytes was regulated by short-term nutritional stress both in vivo and in vitro. The postnatal development of BAT was impaired in SKO mice, which resulted in drastically reduced BAT mass and decreased expression of the thermogenic protein Ucp1 in 24-week-old mice fed with CD. After HFD feeding, the iWAT and BAT mass of SKO mice were significantly decreased, causing ectopic lipid accumulation in the liver, which was associated with insulin resistance and glucose intolerance. Upon cold exposure, the expression of thermogenic genes and proteins was markedly reduced in BAT and iWAT of SKO mice, accompanied by abnormal mitochondrial structure and induced autophagy. Consistently, thermogenic program and mitochondrial oxidative phosphorylation were reduced in survivin-depleted brown and beige adipocytes in vitro.
CONCLUSIONS
Our findings showed that survivin could be regulated by nutritional stress in adipocytes and revealed a new role of survivin in maintaining normal BAT mass and positively regulating the thermogenic program and mitochondrial oxidative phosphorylation.
Topics: Adipocytes, Brown; Adipose Tissue, Brown; Animals; Homeostasis; Mice; Mice, Knockout; Survivin
PubMed: 35114418
DOI: 10.1016/j.molmet.2022.101446 -
Cell Death & Disease Sep 2022Ubiquitin-specific protease 1 (USP1) is a deubiquitinase involved in DNA damage repair by modulating the ubiquitination of major regulators, such as PCNA and FANCD2....
Ubiquitin-specific protease 1 (USP1) is a deubiquitinase involved in DNA damage repair by modulating the ubiquitination of major regulators, such as PCNA and FANCD2. Because USP1 is highly expressed in many cancers, dysregulation of USP1 contributes to cancer therapy. However, the role of USP1 and the mechanisms underlying chemotherapy remain unclear. In this study, we found high USP1 expression in tumor tissues and that it correlated with poor prognosis in RCC. Mechanistically, USP1 enhanced survivin stabilization by removing ubiquitin. Pharmacological inhibitors (ML23 and pimozide) and siRNA targeting USP1 induced downregulation of survivin expression. In addition, ML323 upregulated DR5 expression by decreasing miR-216a-5p expression at the post-transcriptional level, and miR-216a-5p mimics suppressed the upregulation of DR5 by ML323. Inhibition of USP1 sensitized cancer cells. Overexpression of survivin or knockdown of DR5 markedly prevented the co-treatment with ML323 and TRAIL-induced apoptosis. These results of in vitro were proved in a mouse xenograft model, in which combined treatment significantly reduced tumor size and induced survivin downregulation and DR5 upregulation. Furthermore, USP1 and survivin protein expression showed a positive correlation, whereas miR-216a-5p and DR5 were inversely correlated in RCC tumor tissues. Taken together, our results suggest two target substrates of USP1 and demonstrate the involvement of survivin and DR5 in USP1-targeted chemotherapy.
Topics: Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Renal Cell; Cell Line, Tumor; Deubiquitinating Enzymes; Down-Regulation; Humans; Kidney Neoplasms; Mice; MicroRNAs; Pimozide; Proliferating Cell Nuclear Antigen; RNA, Small Interfering; Receptors, TNF-Related Apoptosis-Inducing Ligand; Survivin; Ubiquitin-Specific Proteases; Ubiquitins; Up-Regulation
PubMed: 36153316
DOI: 10.1038/s41419-022-05271-0 -
Critical Reviews in Oncogenesis 2017Despite significant clinical and basic science advancements, cancer remains a devastating disease that affects people of all ages, races, and backgrounds. The... (Review)
Review
Despite significant clinical and basic science advancements, cancer remains a devastating disease that affects people of all ages, races, and backgrounds. The pathogenesis of cancer has recently been described to result from eight biological capabilities or hallmarks and two enabling characteristics. These eight hallmarks are: deregulation of cellular energetics, avoiding immune destruction, enabling replicative immortality, inducing angiogenesis, sustaining proliferative signaling, evading growth suppressors, resisting cell death, and activating invasion and metastasis. The enabling characteristics are: genome instability and mutation and tumor-promoting inflammation. Survivin, the fourth most common transcript found in cancer cells, is a protein that is thought to be involved in the enhanced proliferation, survival, and metastasis and possibly other key hallmarks of cancer cells. Understanding how this gene is turned on and off is vitally important for attempt improving cancer management and therapy. Our work has identified a novel transcriptional regulator of survivin called Yin Yang 1 (YY1), which has been observed to activate some gene promoters and repress others and is gaining increasing interest as a target of cancer therapy. Our work shows for the first time that YY1 represses survivin transcription by physically interacting with the survivin promoter. Furthermore, YY1 appears to contribute to basal survivin transcriptional activity, indicating that disruption of its binding may in part contribute to survivin overexpression after cellular stress events including chemotherapy and radiotherapy.
Topics: Cell Movement; Cell Proliferation; Gene Expression Regulation, Neoplastic; Genomic Instability; Humans; Mutation; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms; Neovascularization, Pathologic; Survivin; YY1 Transcription Factor
PubMed: 29604934
DOI: 10.1615/CritRevOncog.2017020836 -
Translational Vision Science &... Feb 2022This study aims to elucidate the role and mechanism of survivin and FOXP1 in scarring after glaucoma surgery and to evaluate the prevention and treatment of excessive...
PURPOSE
This study aims to elucidate the role and mechanism of survivin and FOXP1 in scarring after glaucoma surgery and to evaluate the prevention and treatment of excessive wound healing and scar formation in an in vitro model of glaucoma filtration surgery.
METHODS
Human Tenon's capsule fibroblasts (HTFs) were used with TGF-β to establish an in vitro cell model after glaucoma, observe survivin expression in the cell model, and observe HTFs proliferation after treatment with survivin inhibitor YM155 and the expression of α-SMA and collagen type I. In addition, the effects of survivin and cell proliferation in HTFs after knockdown of FOXP1 were observed by Western blot analysis.
RESULTS
Survivin was upregulated in HTFs after glaucoma surgery, and it could promote the cell proliferation of HTFs. After treatment with its inhibitor YM155, the cell proliferation of HTFs was inhibited, and the expression of α-SMA and collagen type I were decreased. The results showed that in knockdown of FOXP1, the expression of survivin was downregulated, and the cell proliferation of HTFs was significantly reduced.
CONCLUSIONS
This study demonstrates that targeting survivin with an inhibitory YM155 reduced fibrosis and the extracellular matrix (ECM), and it was regulated by the FOXP1 transcription factor. These results suggest that survivin could be a potential target for treating scar formation after glaucoma surgery.
TRANSLATIONAL RELEVANCE
Together with the results from previous survivin and FOXP1 preclinical studies, these data support the evaluation of this gene therapy candidate in clinical trials as a potential durable treatment for antiscarring of glaucoma surgery.
Topics: Cells, Cultured; Cicatrix; Collagen Type I; Forkhead Transcription Factors; Glaucoma; Humans; Repressor Proteins; Survivin; Transcription Factors
PubMed: 35142784
DOI: 10.1167/tvst.11.2.19 -
International Journal of Cancer Sep 2007Although disease management of head and neck squamous cell carcinomas (HNSCC) has improved significantly, therapy resistance leading to tumor recurrence still... (Review)
Review
Although disease management of head and neck squamous cell carcinomas (HNSCC) has improved significantly, therapy resistance leading to tumor recurrence still counteracts improvement of long-term survival. Consequently, identification of molecular markers that signal increased risk of treatment failure or, which can be exploited by targeted therapy, is urgently needed. Survivin is strongly expressed in HNSCC, and its proposed dual role as an apoptosis inhibitor and a mitotic effector positioned survivin in the front line of cancer research. Notably, survivin is detected as a cytoplasmic and as a nuclear protein in HNSCC patients, which stimulated numerous studies to investigate and to speculate on the functional and prognostic significance of its dynamic localization. This review focuses on our current understanding of the molecular mechanisms regulating survivin's intracellular localization and discusses its potential prognostic and therapeutic relevance for head and neck cancer.
Topics: Animals; Biomarkers, Tumor; Head and Neck Neoplasms; Humans; Inhibitor of Apoptosis Proteins; Microtubule-Associated Proteins; Neoplasm Proteins; Prognosis; Survivin
PubMed: 17617794
DOI: 10.1002/ijc.22941 -
Scientific Reports Nov 2022Overexpression of survivin is frequently observed in human malignancies and is associated with poor prognosis. The present study found that survivin is highly expressed...
Overexpression of survivin is frequently observed in human malignancies and is associated with poor prognosis. The present study found that survivin is highly expressed in nasopharyngeal carcinoma (NPC) tumor tissues. Depleting survivin with shRNA inhibited cell viability, colony formation, and in vivo tumorigenesis of NPC cells. With a natural product screening, we identified Butein as a potential anti-tumor compound for NPC by reducing survivin protein level. Butein shortened the half-life of survivin and enhanced ubiquitination-mediated degradation. The mechanism study showed that Butein promoted the interaction between survivin and E3 ligase Fbxl7, and the knockdown of Fbxl7 compromised Butein-induced survivin ubiquitination. Butein suppressed the Akt-Wee1-CDK1 signaling and decreased survivin Thr34 phosphorylation, facilitating E3 ligase Fbxl7-mediated survivin ubiquitination and degradation. Moreover, Butein exhibited a strong in vivo anti-tumor activity, as the tumor volume of Butein-treated xenografts was reduced significantly. Butein alone or combined with cisplatin (CDDP) overcame chemoresistance in NPC xenograft tumors. Overall, our data indicate that Butein is a promising anti-tumor agent for NPC treatment.
Topics: Humans; Survivin; Drug Resistance, Neoplasm; Ubiquitination; Ubiquitin-Protein Ligases; Nasopharyngeal Carcinoma; Cisplatin; Nasopharyngeal Neoplasms
PubMed: 36450751
DOI: 10.1038/s41598-022-21839-4