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Journal of Translational Medicine Oct 2022Pancreatic adenocarcinoma (PAAD) is one of the most common malignant tumors of the digestive tract. Pyroptosis is a newly discovered programmed cell death that...
BACKGROUND
Pancreatic adenocarcinoma (PAAD) is one of the most common malignant tumors of the digestive tract. Pyroptosis is a newly discovered programmed cell death that highly correlated with the prognosis of tumors. However, the prognostic value of pyroptosis in PAAD remains unclear.
METHODS
A total of 178 pancreatic cancer PAAD samples and 167 normal samples were obtained from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases. The "DESeq2" R package was used to identify differntially expressed pyroptosis-related genes between normal pancreatic samples and PAAD samples. The prognostic model was established in TCGA cohort based on univariate Cox and the least absolute shrinkage and selection operator (LASSO) Cox regression analyses, which was validated in test set from Gene Expression Omnibus (GEO) cohort. Univariate independent prognostic analysis and multivariate independent prognostic analysis were used to determine whether the risk score can be used as an independent prognostic factor to predict the clinicopathological features of PAAD patients. A nomogram was used to predict the survival probability of PAAD patients, which could help in clinical decision-making. The R package "pRRophetic" was applied to calculate the drug sensitivity of each samples from high- and low-risk group. Tumor immune infiltration was investigated using an ESTIMATE algorithm. Finally, the pro-tumor phenotype of GSDMC was explored in PANC-1 and CFPAC-1 cells.
RESULT
On the basis of univariate Cox and LASSO regression analyses, we constructed a risk model with identified five pyroptosis-related genes (IL18, CASP4, NLRP1, GSDMC, and NLRP2), which was validated in the test set. The PAAD samples were divided into high-risk and low-risk groups on the basis of the risk score's median. According to Kaplan Meier curve analysis, samples from high-risk groups had worse outcomes than those from low-risk groups. The time-dependent receiver operating characteristics (ROC) analysis revealed that the risk model could predict the prognosis of PAAD accurately. A nomogram accompanied by calibration curves was presented for predicting 1-, 2-, and 3-year survival in PAAD patients. More importantly, 4 small molecular compounds (A.443654, PD.173074, Epothilone. B, Lapatinib) were identified, which might be potential drugs for the treatment of PAAD patients. Finally, the depletion of GSDMC inhibits the proliferation, invasion, and migration of pancreatic adenocarcinoma cells.
CONCLUSION
In this study, we developed a pyroptosis-related prognostic model based on IL18, CASP4, NLRP1, NLRP2, and GSDMC , which may be helpful for clinicians to make clinical decisions for PAAD patients and provide valuable insights for individualized treatment. Our result suggest that GSDMC may promote the proliferation and migration of PAAD cell lines. These findings may provide new insights into the roles of pyroptosis-related genes in PAAD, and offer new therapeutic targets for the treatment of PAAD.
Topics: Adenocarcinoma; Biomarkers, Tumor; DNA-Binding Proteins; Epothilones; Gene Expression Regulation, Neoplastic; Humans; Interleukin-18; Lapatinib; Pancreatic Neoplasms; Pore Forming Cytotoxic Proteins; Prognosis; Pyroptosis
PubMed: 36199146
DOI: 10.1186/s12967-022-03632-z -
Journal of Translational Medicine Oct 2022Liver carcinoma generally presents as an immunosuppressive microenvironment that promotes tumor evasion. The intercellular crosstalk of immune cells significantly...
BACKGROUND
Liver carcinoma generally presents as an immunosuppressive microenvironment that promotes tumor evasion. The intercellular crosstalk of immune cells significantly influences the construction of an immunosuppressive microenvironment. This study aimed to investigate the important interactions between immune cells and their targeting drugs in liver carcinoma, by using single-cell and bulk transcriptomic data.
METHODS
Single-cell and bulk transcriptomic data were retrieved from Gene Expression Omnibus (GSE159977, GSE136103, and GSE125449) and The Cancer Genome Atlas (TGCA-LIHC), respectively. Quality control, dimension reduction, clustering, and annotation were performed according to the Scanpy workflow based on Python. Cell-cell interactions were explored using the CellPhone database and CellChat. Trajectory analysis was executed using a partition-based graph abstraction method. The transcriptomic factors (TFs) were predicted using single-cell regulatory network inference and clustering (SCENIC). The target genes from TFs were used to establish a related score based on the TCGA cohort; this score was subsequently validated by survival, gene set enrichment, and immune cell infiltration analyses. Drug prediction was performed based on the Cancer Therapeutics Response Portal and PRISM Repurposing datasets.
RESULTS
Thirty-one patients at four different states, including health, hepatitis, cirrhosis, and cancer, were enrolled in this study. After dimension reduction and clustering, twenty-two clusters were identified. Cell-cell interaction analyses indicated that macrophage-naive CD4 + T cell interaction significantly affect cancerous state. In brief, macrophages interact with naive CD4 + T cells via different pathways in different states. The results of SCENIC indicated that macrophages present in cancer cells were similar to those present during cirrhosis. A macrophage-naive CD4 + T cell (MNT) score was generated by the SCENIC-derived target genes. Based on the MNT score, five relevant drugs (inhibitor of polo-like kinase 1, inhibitor of kinesin family member 11, dabrafenib, ispinesib, and epothilone-b) were predicted.
CONCLUSIONS
This study reveals the crucial role of macrophage-naive CD4 + T cell interaction in the immunosuppressive microenvironment of liver carcinoma. Tumor-associated macrophages may be derived from cirrhosis and can initiate liver carcinoma. Predictive drugs that target the macrophage-naive CD4 + T cell interaction may help to improve the immunosuppressive microenvironment and prevent immune evasion. The relevant mechanisms need to be further validated in experiments and cohort studies.
Topics: Biomarkers, Tumor; Carcinoma, Hepatocellular; Cell Communication; Epothilones; Humans; Kinesins; Liver Cirrhosis; Liver Neoplasms; Macrophages; T-Lymphocytes; Transcriptome; Tumor Microenvironment
PubMed: 36221095
DOI: 10.1186/s12967-022-03675-2 -
Frontiers in Immunology 2022M2-like tumor-associated macrophages (M2-like TAMs) have important roles in the progression and therapeutics of cancers. We aimed to detect novel M2-like TAM-related...
M2-like tumor-associated macrophage-related biomarkers to construct a novel prognostic signature, reveal the immune landscape, and screen drugs in hepatocellular carcinoma.
BACKGROUND
M2-like tumor-associated macrophages (M2-like TAMs) have important roles in the progression and therapeutics of cancers. We aimed to detect novel M2-like TAM-related biomarkers in hepatocellular carcinoma (HCC) integrative analysis of single-cell RNA-seq (scRNA-seq) and bulk RNA-seq data to construct a novel prognostic signature, reveal the "immune landscape", and screen drugs in HCC.
METHODS
M2-like TAM-related genes were obtained by overlapping the marker genes of TAM identified from scRNA-seq data and M2 macrophage modular genes identified by weighted gene co-expression network analysis (WGCNA) using bulk RNA-seq data. Univariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression analyses were carried out to screen prognostic genes from M2-like TAM-related genes, followed by a construction of a prognostic signature, delineation of risk groups, and external validation of the prognostic signature. Analyses of immune cells, immune function, immune evasion scores, and immune-checkpoint genes between high- and low-risk groups were done to further reveal the immune landscape of HCC patients. To screen potential HCC therapeutic agents, analyses of gene-drug correlation and sensitivity to anti-cancer drugs were conducted.
RESULTS
A total of 127 M2-like TAM-related genes were identified by integrative analysis of scRNA-seq and bulk-seq data. PDLIM3, PAM, PDLIM7, FSCN1, DPYSL2, ARID5B, LGALS3, and KLF2 were screened as prognostic genes in HCC by univariate Cox regression and LASSO regression analyses. Then, a prognostic signature was constructed and validated based on those genes for predicting the survival of HCC patients. In terms of drug screening, expression of PAM and LGALS3 was correlated positively with sensitivity to simvastatin and ARRY-162, respectively. Based on risk grouping, we predicted 10 anticancer drugs with high sensitivity in the high-risk group, with epothilone B having the lowest half-maximal inhibitory concentration among all drugs tested.
CONCLUSIONS
Our findings enhance understanding of the M2-like TAM-related molecular mechanisms involved in HCC, reveal the immune landscape of HCC, and provide potential targets for HCC treatment.
Topics: Biomarkers, Tumor; Carcinoma, Hepatocellular; Carrier Proteins; Galectin 3; Gene Expression Regulation, Neoplastic; Humans; Liver Neoplasms; Microfilament Proteins; Prognosis; Simvastatin; Tumor-Associated Macrophages
PubMed: 36177006
DOI: 10.3389/fimmu.2022.994019 -
The Oncologist 2001Ovarian cancer remains the most lethal gynecologic malignancy in women in the United States. Studies from this year's American Society of Clinical Oncology more clearly... (Review)
Review
Ovarian cancer remains the most lethal gynecologic malignancy in women in the United States. Studies from this year's American Society of Clinical Oncology more clearly defined the role of chemotherapy in women with early stage disease and now suggest that essentially all women with invasive disease should receive chemotherapy that contains carboplatin. Studies in women with advanced disease continue to support the use of carboplatin and paclitaxel in the treatment of women with newly diagnosed disease although early data suggest that carboplatin and docetaxel might be an acceptable alternative. Platinum-resistant disease remains a therapeutic challenge. Small molecules that inhibit the function of the epidermal growth factor receptor, such as OSI-774, and novel classes of chemotherapeutic agents, including the acylfulvene MGI-114 and epothilone B and its analogue, BMS247550, all warrant further study in this disease.
Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Female; Humans; Ovarian Neoplasms
PubMed: 11524550
DOI: 10.1634/theoncologist.6-4-327 -
Frontiers in Cellular Neuroscience 2020The search for drugs that can facilitate axonal regeneration and elongation following peripheral nerve injury has been an area of increasing interest in recent years....
The search for drugs that can facilitate axonal regeneration and elongation following peripheral nerve injury has been an area of increasing interest in recent years. Epothilone B (EpoB) is an FDA-approved antineoplastic agent, which shows the capacity to induce α-tubulin polymerization and to improve the stability of microtubules. Recently, it has been increasingly recognized that EpoB has a regenerative effect in the central nervous system. However, the information currently available regarding the potential therapeutic effect of EpoB on peripheral nerve regeneration is limited. Here, we used a rat sciatic crush injury model system to determine that EpoB strikingly improved axonal regeneration and recovery of function. Also, EpoB (1 nM) did not result in significant apoptosis in Schwann cells (SCs) and showed little effect on their viability either. Interestingly, EpoB (1 nM) significantly enhanced migration in SCs, which was inhibited by autophagy inhibitors 3-methyladenine (3-MA). Since PI3K/Akt signaling has been implicated in regulating autophagy, we further examined the involvement of PI3K/Akt in the process of EpoB-induced SC migration. We found that EpoB (1 nM) significantly inhibited phosphorylation of PI3K and Akt in SCs. Further studies showed that both EpoB-enhanced migration and autophagy were increased/inhibited by inhibition/activation of PI3K/Akt signaling with LY294002 or IGF-1. In conclusion, EpoB can promote axonal regeneration following peripheral nerve injury by enhancing the migration of SCs, with this activity being controlled by PI3K/Akt signaling-mediated autophagy in SCs. This underscores the potential therapeutic value of EpoB in enhancing regeneration and functional recovery in cases of peripheral nerve injury.
PubMed: 32528253
DOI: 10.3389/fncel.2020.00143 -
International Journal of Molecular... Nov 2023No matter what treatment is used after nerve transection, a complete cure is impossible, so basic and clinical research is underway to find a cure. As part of this... (Review)
Review
No matter what treatment is used after nerve transection, a complete cure is impossible, so basic and clinical research is underway to find a cure. As part of this research, autophagy is being investigated for its role in nerve regeneration. Here, we review the existing literature regarding the involvement and significance of autophagy in peripheral nerve injury and regeneration. A comprehensive literature review was conducted to assess the induction and role of autophagy in peripheral nerve injury and subsequent regeneration. Studies were included if they were prospective or retrospective investigations of autophagy and facial or peripheral nerves. Articles not mentioning autophagy or the facial or peripheral nerves, review articles, off-topic articles, and those not written in English were excluded. A total of 14 peripheral nerve studies that met these criteria, including 11 involving sciatic nerves, 2 involving facial nerves, and 1 involving the inferior alveolar nerve, were included in this review. Studies conducted on rats and mice have demonstrated activation of autophagy and expression of related factors in peripheral nerves with or without stimulation of autophagy-inducing factors such as rapamycin, curcumin, three-dimensional melatonin nerve scaffolds, CXCL12, resveratrol, nerve growth factor, lentinan, adipose-derived stem cells and melatonin, basic fibroblast growth factor, and epothilone B. Among the most studied of these factors in relation to degeneration and regeneration of facial and sciatic nerves are LC3II/I, PI3K, mTOR, Beclin-1, ATG3, ATG5, ATG7, ATG9, and ATG12. This analysis indicates that autophagy is involved in the process of nerve regeneration following facial and sciatic nerve damage. Inadequate autophagy induction or failure of autophagy responses can result in regeneration issues after peripheral nerve damage. Animal studies suggest that autophagy plays an important role in peripheral nerve degeneration and regeneration.
Topics: Rats; Mice; Animals; Peripheral Nerve Injuries; Melatonin; Prospective Studies; Retrospective Studies; Peripheral Nerves; Sciatic Nerve; Nerve Regeneration; Autophagy
PubMed: 38003409
DOI: 10.3390/ijms242216219 -
Aging Jun 2020Inflammatory osteolysis is a common osteolytic specificity that occurs during infectious orthopaedic surgery and is characterized by an imbalance in bone homeostasis due...
Inflammatory osteolysis is a common osteolytic specificity that occurs during infectious orthopaedic surgery and is characterized by an imbalance in bone homeostasis due to excessive osteoclast bone resorption activity. Epothilone B (Epo B) induced α-tubulin polymerization and enhanced microtubule stability, which also played an essential role in anti-inflammatory effect on the regulation of many diseases. However, its effects on skeletal system have rarely been investigated. Our study demonstrated that Epo B inhibited osteoclastogenesis and prevented inflammatory osteolysis Further analysis showed that Epo B also markedly induced mature osteoclasts apoptosis during osteoclastogenesis. Mechanistically, Epo B directly suppressed osteoclastogenesis by the inhibitory regulation of the phosphorylation and activation of PI3K/Akt/STAT3 signaling directly, and the suppressive regulation of the CD9/gp130/STAT3 signaling pathway indirectly. The negative regulatory effect on STAT3 signaling further restrained the translocation of NF-κB p65 and NFATc1 from the cytosol to the nuclei during RANKL stimulation. Additionally, the expression of osteoclast specific genes was also significantly attenuated during osteoclast fusion and differentiation. Taken together, these findings illustrated that Epo B protected against LPS-induced bone destruction through inhibiting osteoclastogenesis via regulating the STAT3 dependent signaling pathway.
Topics: Animals; Apoptosis; Cell Differentiation; Cell Nucleus; Cytosol; Disease Models, Animal; Epothilones; Female; Femur; Humans; Lipopolysaccharides; Mice; NF-kappa B; NFATC Transcription Factors; Osteoclasts; Osteogenesis; Osteolysis; Primary Cell Culture; RANK Ligand; RAW 264.7 Cells; STAT3 Transcription Factor; Signal Transduction; Transcription Factor RelA; X-Ray Microtomography
PubMed: 32527985
DOI: 10.18632/aging.103337 -
Oncology (Williston Park, N.Y.) Apr 2008Epothilones are cytotoxic compounds that function in a similar fashion to paclitaxel and show promise for the treatment of a variety of cancers by inducing microtubule... (Review)
Review
Epothilones are cytotoxic compounds that function in a similar fashion to paclitaxel and show promise for the treatment of a variety of cancers by inducing microtubule bundling and apoptotic cell death. However, their mechanism of microtubule binding is different from that of paclitaxel, which makes epothilones an attractive drug class for patients with taxane-resistant malignancies. As taxane resistance remains a significant barrier in the treatment of a variety of cancers, it is important to understand epothilones and their indications. Several epothilone compounds, including ixabepilone (BMS-247550, aza-epothilone B, Ixempra), patupilone (EPO906, epothilone B), KOS-862 (desoxyepothilone B, epothilone D), BMS-310705, ZK-EPO (ZK-219477), nd KOS-1584, have been testedf or the treatment of a variety of solid tumor types. Recently, ixabepilone became the first epothilone to be approved by the US Food and Drug Administration, for the treatment of metastatic or locally advanced breast cancer as monotherapy or in combination with capecitabine (Xeloda) after other treatments have failed. This article reviews recent findings from clinical trials of epothilones and discusses future directions for the use of these agents in cancer therapy, with a focus on the two most-studied epothilones to date: ixabepilone and patupilone.
Topics: Antineoplastic Agents; Breast Neoplasms; Epothilones; Humans; Neoplasms; Tubulin Modulators
PubMed: 18472615
DOI: No ID Found -
Neural Plasticity 2016Several studies have demonstrated the therapeutic potential of applying microtubule- (MT-) stabilizing agents (MSAs) that cross the blood-brain barrier to promote axon...
Several studies have demonstrated the therapeutic potential of applying microtubule- (MT-) stabilizing agents (MSAs) that cross the blood-brain barrier to promote axon regeneration and prevent axonal dystrophy in rodent models of spinal cord injury and neurodegenerative diseases. Paradoxically, administration of MSAs, which have been widely prescribed to treat malignancies, is well known to cause debilitating peripheral neuropathy and axon degeneration. Despite the growing interest of applying MSAs to treat the injured or degenerating central nervous system (CNS), consequences of MSA exposure to neurons in the central and peripheral nervous system (PNS) have not been thoroughly investigated. Here, we have examined and compared the effects of a brain-penetrant MSA, epothilone B, on cortical and sensory neurons in culture and show that epothilone B exhibits both beneficial and detrimental effects, depending on not only the concentration of drug but also the type and age of a neuron, as seen in clinical settings. Therefore, to exploit MSAs to their full benefit and minimize unwanted side effects, it is important to understand the properties of neuronal MTs and strategies should be devised to deliver minimal effective concentration directly to the site where needed.
Topics: Age Factors; Animals; Animals, Newborn; Brain; Cells, Cultured; Epothilones; Female; Mice; Mice, Inbred ICR; Microtubules; Neurons; Tubulin Modulators
PubMed: 27872763
DOI: 10.1155/2016/5056418 -
Scientific Reports Oct 2022SMER28 originated from a screen for small molecules that act as modulators of autophagy. SMER28 enhanced the clearance of autophagic substrates such as mutant...
SMER28 originated from a screen for small molecules that act as modulators of autophagy. SMER28 enhanced the clearance of autophagic substrates such as mutant huntingtin, which was additive to rapamycin-induced autophagy. Thus, SMER28 was established as a positive regulator of autophagy acting independently of the mTOR pathway, increasing autophagosome biosynthesis and attenuating mutant huntingtin-fragment toxicity in cellular- and fruit fly disease models, suggesting therapeutic potential. Despite many previous studies, molecular mechanisms mediating SMER28 activities and its direct targets have remained elusive. Here we analyzed the effects of SMER28 on cells and found that aside from autophagy induction, it significantly stabilizes microtubules and decelerates microtubule dynamics. Moreover, we report that SMER28 displays neurotrophic and neuroprotective effects at the cellular level by inducing neurite outgrowth and protecting from excitotoxin-induced axon degeneration. Finally, we compare the effects of SMER28 with other autophagy-inducing or microtubule-stabilizing drugs: whereas SMER28 and rapamycin both induce autophagy, the latter does not stabilize microtubules, and whereas both SMER28 and epothilone B stabilize microtubules, epothilone B does not stimulate autophagy. Thus, the effect of SMER28 on cells in general and neurons in particular is based on its unique spectrum of bioactivities distinct from other known microtubule-stabilizing or autophagy-inducing drugs.
Topics: Neuroprotection; Neuroprotective Agents; Neurotoxins; Autophagy; TOR Serine-Threonine Kinases; Sirolimus; Microtubules
PubMed: 36284196
DOI: 10.1038/s41598-022-20563-3