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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 -
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 -
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 -
Cell Cycle (Georgetown, Tex.) Jun 2023Isoalantolactone (Iso) is a bioactive lactone isolated from the root of Inula helenium L, which has been reported to have many pharmacological effects. To investigate...
Isoalantolactone (Iso) is a bioactive lactone isolated from the root of Inula helenium L, which has been reported to have many pharmacological effects. To investigate the role and mechanism of isoalantolactone in chronic myeloid leukemia (CML), we first investigated isoalantolactone's anti-proliferative effects on imatinib-sensitive and imatinib-resistant CML cells by CCK8. Flow cytometry was used to detect isoalantolactone-induced cell apoptosis. Survivin was overexpressed in KBM5 and KBM5 cells using the lentivirus vector pSIN-3×flag-PURO. In KBM5 and KBM5 cells, shRNA was used to knockdown survivin. Cellular Thermal Shift Assay (CETSA) was used to detect the interaction between isoalantolactone and survivin. The ubiquitin of survivin induced by isoalantolactone was detected through immunoprecipitation. Quantitative polymerase-chain reaction (Q-PCR) and western blotting were used to detect the levels of mRNA and protein. Isoalantolactone inhibits the proliferation and promotes apoptosis of imatinib-resistant CML cells. Although isoalantolactone inhibits the proteins of BCR-ABL and survivin, it cannot inhibit survivin and BCR-ABL mRNA levels. Simultaneously, it was shown that isoalantolactone can degrade survivin protein by increasing ubiquitination. It was demonstrated that isoalantolactone-induced survivin mediated downregulation of BCR-ABL protein. It was also revealed that isoalantolactone triggered BCR-ABL protein degradation via caspase-3. Altogether, isoalantolactone inhibits survivin through the ubiquitin proteasome pathway, and mediates BCR-ABL downregulation in a caspase-3 dependent manner. These data suggest that isoalantolactone is a natural compound, which can be used as a potential drug to treat TKI-resistant CML.
Topics: Humans; Imatinib Mesylate; Survivin; Caspase 3; Drug Resistance, Neoplasm; Cell Proliferation; Fusion Proteins, bcr-abl; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Apoptosis; RNA, Messenger; Ubiquitins; Cell Line, Tumor
PubMed: 37202916
DOI: 10.1080/15384101.2023.2209963 -
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 -
World Journal of Surgical Oncology Feb 2015Colorectal cancer (CRC) is the most common cause of cancer death worldwide. Numerous studies have identified the roles of survivin -31 G/C and angiotensin-converting... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Colorectal cancer (CRC) is the most common cause of cancer death worldwide. Numerous studies have identified the roles of survivin -31 G/C and angiotensin-converting enzyme insertion/deletion (ACE I/D) polymorphisms in CRC risk; however, the results remain inconclusive. This study was to investigate associations between these two polymorphisms and CRC susceptibility.
METHODS
A comprehensive literature search was conducted to collect relevant case-control studies published between 2000 and 2014. The extracted data were statistically analyzed, and the odds ratios (ORs) with 95% confidence intervals (CIs) were employed to estimate the strength of association.
RESULTS
A total of 11 studies were included in the meta-analysis. For survivin G/C polymorphism, six articles reported 1,840 cases and 1,804 controls. Overall, we found the frequency of C allele is higher in CRC cases than that in the healthy controls (57.2% vs. 48.0%), and C allele significantly increased the risk of CRC compared to G allele in allele model (OR = 1.46, 95% CI = 1.33-1.60, P < 0.00001). This association was also found in other genetic models (P < 0.00001). Stratified analysis by ethnicity showed significant association in each genetic model among the Asian population. For ACE I/D polymorphism, five studies included 758 cases and 6,755 controls. No significant association was found in any genetic models.
CONCLUSIONS
Our results showed that survivin -31 G/C polymorphism might contribute to risk of CRC, especially in the Asian populations. However, the ACE I/D polymorphism is not a genetic factor concerning the risk for CRC. More studies with larger sample sizes are required in the future.
Topics: Case-Control Studies; Colorectal Neoplasms; Genetic Predisposition to Disease; Humans; Inhibitor of Apoptosis Proteins; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Prognosis; Risk Factors; Survivin
PubMed: 25889770
DOI: 10.1186/s12957-015-0461-5 -
Clinical and Translational Medicine May 2022Pancreatic ductal adenocarcinoma (PDAC), a difficult-to-treat cancer, is expected to become the second-largest cause of cancer-related deaths by 2030, while colorectal...
FL118, acting as a 'molecular glue degrader', binds to dephosphorylates and degrades the oncoprotein DDX5 (p68) to control c-Myc, survivin and mutant Kras against colorectal and pancreatic cancer with high efficacy.
BACKGROUND
Pancreatic ductal adenocarcinoma (PDAC), a difficult-to-treat cancer, is expected to become the second-largest cause of cancer-related deaths by 2030, while colorectal cancer (CRC) is the third most common cancer and the third leading cause of cancer deaths. Currently, there is no effective treatment for PDAC patients. The development of novel agents to effectively treat these cancers remains an unmet clinical need. FL118, a novel anticancer small molecule, exhibits high efficacy against cancers; however, the direct biochemical target of FL118 is unknown.
METHODS
FL118 affinity purification, mass spectrometry, Nanosep centrifugal device and isothermal titration calorimetry were used for identifying and confirming FL118 binding to DDX5/p68 and its binding affinity. Immunoprecipitation (IP), western blots, real-time reverse transcription PCR, gene silencing, overexpression (OE) and knockout (KO) were used for analysing gene/protein function and expression. Chromatin IP was used for analysing protein-DNA interactions. The 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromid assay and human PDAC/CRC cell/tumour models were used for determining PDAC/CRC cell/tumour in vitro and in vivo growth.
RESULTS
We discovered that FL118 strongly binds to dephosphorylates and degrades the DDX5 oncoprotein via the proteasome degradation pathway without decreasing DDX5 mRNA. Silencing and OE of DDX5 indicated that DDX5 is a master regulator for controlling the expression of multiple oncogenic proteins, including survivin, Mcl-1, XIAP, cIAP2, c-Myc and mutant Kras. Genetic manipulation of DDX5 in PDAC cells affects tumour growth. PDAC cells with DDX5 KO are resistant to FL118 treatment. Our human tumour animal model studies further indicated that FL118 exhibits high efficacy to eliminate human PDAC and CRC tumours that have a high expression of DDX5, while FL118 exhibits less effectiveness in PDAC and CRC tumours with low DDX5 expression.
CONCLUSION
DDX5 is a bona fide FL118 direct target and can act as a biomarker for predicting PDAC and CRC tumour sensitivity to FL118. This would greatly impact FL118 precision medicine for patients with advanced PDAC or advanced CRC in the clinic. FL118 may act as a 'molecular glue degrader' to directly glue DDX5 and ubiquitination regulators together to degrade DDX5.
Topics: Animals; Benzodioxoles; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Colorectal Neoplasms; DEAD-box RNA Helicases; Humans; Indolizines; Oncogene Proteins; Pancreatic Neoplasms; Proto-Oncogene Proteins p21(ras); Survivin
PubMed: 35604033
DOI: 10.1002/ctm2.881 -
Journal of Colloid and Interface Science Sep 2023In recent years, small interfering RNA (siRNA) has been widely used in the treatment of human diseases, especially tumors, and has shown great appeal. However, the...
In recent years, small interfering RNA (siRNA) has been widely used in the treatment of human diseases, especially tumors, and has shown great appeal. However, the clinical application of siRNA faces several challenges. Insufficient efficacy, poor bioavailability, poor stability, and lack of responsiveness to a single therapy are the main problems affecting tumor therapy. Here, we designed a cell-penetrating peptide (CPP)-modified metal organic framework nanoplatform (named PEG-CPP33@ORI@survivin siRNA@ZIF-90, PEG-CPP33@NPs) for targeted co-delivery of oridonin (ORI), a natural anti-tumor active ingredient) and survivin siRNA in vivo. This can improve the stability and bioavailability of siRNA and the efficacy of siRNA monotherapy. The high drug-loading capacity and pH-sensitive properties of zeolite imidazolides endowed the PEG-CPP33@NPs with lysosomal escape abilities. The Polyethylene glycol (PEG)-conjugated CPP (PEG-CPP33) coating significantly improved the uptake in the PEG-CPP33@NPs in vitro and in vivo. The results showed that the co-delivery of ORI and survivin siRNA greatly enhanced the anti-tumor effect of PEG-CPP33@NPs, demonstrating the synergistic effect between ORI and survivin siRNA. In summary, the novel targeted nanobiological platform loaded with ORI and survivin siRNA presented herein showed great advantages in cancer therapy, and provides an attractive strategy for the synergistic application of chemotherapy and gene therapy.
Topics: Humans; Survivin; RNA, Small Interfering; Cell-Penetrating Peptides; Metal-Organic Frameworks; Neoplasms; Lysosomes; Nanoparticles; Cell Line, Tumor
PubMed: 37207419
DOI: 10.1016/j.jcis.2023.04.126 -
World Journal of Surgical Oncology Dec 2023Multidisciplinary therapy centered on antitumor drugs is indicated in patients with unresectable pancreatic neuroendocrine tumors (PanNET). However, the criteria for...
BACKGROUND
Multidisciplinary therapy centered on antitumor drugs is indicated in patients with unresectable pancreatic neuroendocrine tumors (PanNET). However, the criteria for selection of optimal therapeutic agents is controversial. The aim of this study was to assess the malignancy of PanNET for optimal therapeutic drug selection.
METHODS
Forty-seven patients with PanNET who underwent surgery were reviewed retrospectively, and immunohistochemical characteristics, including expression of GLUT1, SSTR2a, SSTR5, Survivin, X-chromosome-linked inhibitor of apoptosis protein (XIAP), and Caspase3 in the resected specimens, were investigated. Relapse-free survival (RFS) and overall survival (OS) were evaluated with regard to the characteristics using the Kaplan-Meier method and compared with the log-rank test.
RESULTS
GLUT1 expression showed significant correlation with sex (p = 0.036) and mitotic rate (p = 0.048). Survivin and XIAP expression showed significant correlation with T-stage (p = 0.014 and 0.009), p-Stage (p = 0.028 and 0.045), and mitotic rate (p = 0.023 and 0.007). XIAP expression also significantly influenced OS (p = 0.044).
CONCLUSIONS
Survivin and XIAP correlated with grade of malignancy, and expression of XIAP in particular was associated with a poor prognosis. Expression of these proteins may be a useful indicator to select optimal therapeutic agents in PanNET.
Topics: Humans; Survivin; Inhibitor of Apoptosis Proteins; Neuroendocrine Tumors; Retrospective Studies; Glucose Transporter Type 1; Prognosis; Neoplasm Recurrence, Local; X-Linked Inhibitor of Apoptosis Protein; Apoptosis; Pancreatic Neoplasms
PubMed: 38082268
DOI: 10.1186/s12957-023-03267-4 -
Bioscience Reports Jan 2021Survivin is an inhibitor of apoptosis as well as a promoter of cell proliferation. Fibulin-3 is a matrix glycoprotein that displays potential for tumor suppression or...
Survivin is an inhibitor of apoptosis as well as a promoter of cell proliferation. Fibulin-3 is a matrix glycoprotein that displays potential for tumor suppression or propagation. The present study aimed to validate the expression levels of survivin and fibulin-3 in benign and malignant respiratory diseases. This case-control study included 219 patients categorized into five groups. Group A included 63 patients with lung cancer, group B included 63 patients with various benign lung diseases, group D included 45 patients with malignant pleural mesothelioma (MPM), and group E included 48 patients with various benign pleural diseases. Group C included 60 healthy individuals (control group). Serum survivin and fibulin-3 levels were measured by ELISA, whereas their nuclear expressions in the lung and pleura were assessed via Western blot analysis. The results showed significantly higher survivin serum levels and significantly lower fibulin-3 levels in group A compared with in group B and controls (P<0.001). There were significantly higher serum levels of survivin and fibulin-3 in group D compared with in group E and controls (P<0.001), consistent with observed nuclear survivin and fibulin-3 expression levels. Fibulin-3 was determined to have higher value than survivin in discriminating lung cancer from MPM (P<0.05). Survivin and fibulin-3 could be useful diagnostic markers for lung and pleural cancers, and fibulin-3 expression was particularly useful in differentiating lung cancer from MPM.
Topics: Biomarkers; Blotting, Western; Case-Control Studies; Diagnosis, Differential; Enzyme-Linked Immunosorbent Assay; Extracellular Matrix Proteins; Female; Humans; Male; Mesothelioma, Malignant; Middle Aged; Pleural Diseases; Survivin
PubMed: 33226065
DOI: 10.1042/BSR20203097