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Frontiers in Immunology 2022Cellular senescence plays an irreplaceable role in tumorigenesis, progression, and tumor microenvironment (TME) remodeling. However, to date, there is limited research...
A cellular senescence-related classifier based on a tumorigenesis- and immune infiltration-guided strategy can predict prognosis, immunotherapy response, and candidate drugs in hepatocellular carcinoma.
BACKGROUND
Cellular senescence plays an irreplaceable role in tumorigenesis, progression, and tumor microenvironment (TME) remodeling. However, to date, there is limited research delineating the landscape of cellular senescence in hepatocellular carcinoma (HCC), and an improved understanding on the interaction of tumor-associated cellular senescence with HCC prognosis, TME, and response to immunotherapy is warrant.
METHODS
Tumorigenic and immune infiltration-associated senescence genes were determined by weighted gene co-expression network analysis (WGCNA) and the Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data (ESTIMATE) algorithm, and subsequently, a prognostic scoring model (named TIS) was constructed using multiple survival analysis algorithms to classify the senescence-related subtypes of HCC. Gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) were conducted to identify the distinct hallmark pathways between high- and low-risk subtypes. Additionally, we carried out correlation analyses for TIS and clinical traits, senescence-associated secretory phenotype (SASP), immune infiltration and evasion, immune checkpoint factors, drug response, and immunotherapeutic efficacy. External experimental validation was conducted to delineate the association of CPEP3 (a TIS gene) with HCC phenotypes through assays of proliferation, colony formation, and invasion.
RESULTS
A five-gene TIS, composed of NET1, ATP6V0B, MMP1, GTDC1, and CPEB3, was constructed and validated using TCGA and ICGC datasets, respectively, and showed a highly robust and plausible signature for overall survival (OS) prediction of HCC in both training and validation cohorts. Patients in the TIS-high group were accompanied by worse OS, activation of carcinogenetic pathways, infiltration of immunosuppressive cells, exclusion of effector killing cells, overexpression of immunomodulatory genes and SASP, and unsatisfied response to immunotherapy. In response to anticancer drugs, patients in the TIS-high group exhibited enhanced susceptibility to several conventional chemotherapeutic agents (5-fluorouracil, docetaxel, doxorubicin, gemcitabine, and etoposide), as well as several inhibitors of pathways involved in cellular senescence (cell-cycle inhibitors, bromodomain and extraterminal domain family (BET) inhibitors, PI3K-AKT pathway inhibitors, and multikinase inhibitors). Additionally, four putative drugs (palbociclib, JAK3 inhibitor VI, floxuridine, and lestaurtinib) were identified as potential compounds for patients in the TIS-high group. Notably, functional validation showed that CPEB3 knockdown boosted the phenotypes of proliferation, clonogenicity, and invasion in HCC cells, whereas CPEB3 overexpression attenuated these phenotypes.
CONCLUSIONS
Our study provides comprehensive clues demonstrating the role of novel TIS in predicting HCC prognosis, immunotherapeutic response, and candidate drugs. This work highlights the significance of tumorigenesis- and immune infiltration-related cellular senescence in cancer therapy.
Topics: Humans; Carcinoma, Hepatocellular; Phosphatidylinositol 3-Kinases; Liver Neoplasms; Prognosis; Immunotherapy; Carcinogenesis; Immunologic Factors; Cellular Senescence; Tumor Microenvironment; RNA-Binding Proteins; Glycosyltransferases
PubMed: 36458010
DOI: 10.3389/fimmu.2022.974377 -
PloS One 2018Anaplastic thyroid cancer (ATC) is a rare and lethal human malignancy with no known effective therapies in the majority of cases. Despite the use of conventional...
Anaplastic thyroid cancer (ATC) is a rare and lethal human malignancy with no known effective therapies in the majority of cases. Despite the use of conventional treatments such as chemotherapy, radiation and surgical resection, this disease remains almost universally fatal. In the present study, we identified the JAK2 inhibitor Lestaurtinib as a potent compound when testing against 13 ATC cell lines. Lestaurtinib demonstrated a potent antiproliferative effect in vitro at nanomolar concentrations. Furthermore, Lestaurtinib impeded cell migration and the ability to form colonies from single cells using scratch-wound and colony formation assays, respectively. Flow cytometry was used for cell cycle analysis following drug treatment and demonstrated arrest at the G2/M phase of the cell cycle, indicative of a cytostatic effect. In vivo studies using the chick chorioallantoic membrane xenograft models demonstrated that treatment with Lestaurtinib resulted in a significant decrease in endpoint tumor volume and vascularity using power Doppler ultrasound imaging. Overall, this study provides evidence that Lestaurtinib is a potent antiproliferative agent with potential antiangiogenic activity that warrants further investigation as a targeted therapy for ATC.
Topics: Animals; Antineoplastic Agents; Apoptosis; Carbazoles; Cell Cycle; Cell Line, Tumor; Cell Movement; Cell Proliferation; Chick Embryo; Dose-Response Relationship, Drug; Furans; Humans; Janus Kinase 2; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Xenograft Model Antitumor Assays
PubMed: 30419054
DOI: 10.1371/journal.pone.0207152 -
Journal of Cellular and Molecular... Mar 2024Yingxiao Cao, Shiqi Kong, Yuling Xin, Yan Meng, Shuling Shang, Yanhui Qi. Lestaurtinib potentiates TRAIL-induced apoptosis in glioma via CHOP-dependent DR5 induction. J...
Yingxiao Cao, Shiqi Kong, Yuling Xin, Yan Meng, Shuling Shang, Yanhui Qi. Lestaurtinib potentiates TRAIL-induced apoptosis in glioma via CHOP-dependent DR5 induction. J Cell Mol Med. 2020; 24: 7829-7840. https://doi.org/10.1111/jcmm.15415. The above article, published online on 22 May 2020 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the authors, the journal Editor-in-Chief, Stefan Constantinescu, The Foundation for Cellular and Molecular Medicine, and John Wiley and Sons Ltd. The retraction has been agreed upon following an investigation into concerns raised by a third party, which revealed inappropriate duplications of images between this and other articles that were either previously published or published later in the same year in a different scientific context. Thus, the editors consider the conclusions of this manuscript substantially compromised.
PubMed: 38073196
DOI: 10.1111/jcmm.18077 -
International Journal of Molecular... Sep 2022Patients with advanced neuroblastoma (NB) receive multimodal clinical therapy, including the potent anthracycline chemotherapy drug doxorubicin (Dox). The acquisition of...
Patients with advanced neuroblastoma (NB) receive multimodal clinical therapy, including the potent anthracycline chemotherapy drug doxorubicin (Dox). The acquisition of Dox resistance, however, is a major barrier to a sustained response and leads to a poor prognosis in advanced disease states, reinforcing the need to identify and inhibit Dox resistance mechanisms. In this context, we report on the identification and inhibition of a novel Dox resistance mechanism. This mechanism is characterized by the Dox-induced activation of the oncogenic TrkAIII alternative splice variant, resulting in increased Dox resistance, and is blocked by lestaurtinib, entrectinib, and crizotinib tyrosine kinase and LY294002 IP3-K inhibitors. Using time lapse live cell imaging, conventional and co-immunoprecipitation Western blots, RT-PCR, and inhibitor studies, we report that the Dox-induced TrkAIII activation correlates with proliferation inhibition and is CDK1- and Ca-uniporter-independent. It is mediated by ryanodine receptors; involves Ca-dependent interactions between TrkAIII, calmodulin and Hsp90; requires oxygen and oxidation; occurs within assembled ERGICs; and does not occur with fully spliced TrkA. The inhibitory effects of lestaurtinib, entrectinib, crizotinib, and LY294002 on the Dox-induced TrkAIII and Akt phosphorylation and resistance confirm roles for TrkAIII and IP3-K consistent with Dox-induced, TrkAIII-mediated pro-survival IP3K/Akt signaling. This mechanism has the potential to select resistant dormant TrkAIII-expressing NB cells, supporting the use of Trk inhibitors during Dox therapy in TrkAIII-expressing NBs.
Topics: Alternative Splicing; Benzamides; Calmodulin; Cell Line, Tumor; Crizotinib; Doxorubicin; Humans; Indazoles; Neuroblastoma; Oxygen; Proto-Oncogene Proteins c-akt; Receptor, trkA; Ryanodine Receptor Calcium Release Channel
PubMed: 36142807
DOI: 10.3390/ijms231810895 -
PloS One Apr 2011Standard cytotoxic chemotherapy for Hodgkin Lymphoma (HL) has changed little in 30 years; the treatment for patients with relapsed or refractory disease remains...
Standard cytotoxic chemotherapy for Hodgkin Lymphoma (HL) has changed little in 30 years; the treatment for patients with relapsed or refractory disease remains challenging and novel agents are under development. JAK/STAT constitutive activation plays an important role in the pathogenesis of HL. Lestaurtinib is an orally bioavailable multikinase inhibitor that has recently been shown to inhibit JAK2 in myeloproliferative disorders. The potential role of Lestaurtinib in HL therapy is unknown. We have analyzed the effect of Lestaurtinib treatment in five HL cell lines from refractory patients, L-428, L-1236, L-540, HDML-2 and HD-MY-Z. At 48 h, a dose-dependent cell growth inhibition (23%-66% at 300 nM) and apoptotic increment (10%-64% at 300 nM) were observed. Moreover, Lestaurtinib inhibited JAK2, STAT5 and STAT3 phosphorylation and reduced the mRNA expression of its downstream antiapoptotic target Bcl-xL. In addition, we have analyzed the effect of Lestaurtinib treatment in lymph nodes from four classic HL patients. We observed a decrease in cell viability at 24 hours of treatment in three patients (mean decrease of 27% at 300 nM). Our findings provide, for the first time, a molecular rationale for testing JAK2 inhibitors, specifically Lestaurtinib, in HL patients.
Topics: Adult; Apoptosis; Blotting, Western; Carbazoles; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Female; Furans; Hodgkin Disease; Humans; Janus Kinases; Male; Protein Kinase Inhibitors; STAT Transcription Factors
PubMed: 21533094
DOI: 10.1371/journal.pone.0018856 -
Clinical Cancer Research : An Official... Mar 2010Neuroblastoma, a common pediatric tumor of the sympathetic nervous system, is characterized by clinical heterogeneity. The Trk family neurotrophin receptors play an...
PURPOSE
Neuroblastoma, a common pediatric tumor of the sympathetic nervous system, is characterized by clinical heterogeneity. The Trk family neurotrophin receptors play an important role in this behavior. Expression of TrkA is associated with favorable clinical features and outcome, whereas TrkB expression is associated with an unfavorable prognosis. We wanted to determine if the Trk-selective inhibitor lestaurtinib had therapeutic efficacy in a preclinical neuroblastoma model.
EXPERIMENTAL DESIGN
We performed intervention trials of lestaurtinib alone or in combination with other agents in TrkB-overexpressing neuroblastoma xenograft models.
RESULTS
Lestaurtinib alone significantly inhibited tumor growth compared to vehicle-treated animals [P = 0.0004 for tumor size and P = 0.011 for event-free survival (EFS)]. Lestaurtinib also enhanced the antitumor efficacy of the combinations of topotecan plus cyclophosphamide (P < 0.0001 for size and P < 0.0001 for EFS) or irinotecan plus temozolomide (P = 0.011 for size and P = 0.012 for EFS). There was no additive benefit of combining either 13-cis-retinoic acid or fenretinide with lestaurtinib compared to lestaurtinib alone. There was dramatic growth inhibition combining lestaurtinib with bevacizumab (P < 0.0001), but this combination had substantial systemic toxicity.
CONCLUSIONS
We show that lestaurtinib can inhibit the growth of neuroblastoma both in vitro and in vivo and can substantially enhance the efficacy of conventional chemotherapy, presumably by inhibition of the Trk/brain-derived neurotrophic factor autocrine survival pathway. It may also enhance the efficacy of selected biological agents, but further testing is required to rule out unanticipated toxicities. Our data support the incorporation of Trk inhibitors, such as lestaurtinib, in clinical trials of neuroblastoma or other tumors relying on Trk signaling pathways for survival.
Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Carbazoles; Cyclophosphamide; Dacarbazine; Enzyme Activation; Furans; Humans; Irinotecan; Mice; Mice, Nude; Neuroblastoma; Receptor, trkB; Temozolomide; Topotecan; Xenograft Model Antitumor Assays
PubMed: 20179224
DOI: 10.1158/1078-0432.CCR-09-1531 -
Frontiers in Cell and Developmental... 2022Patients diagnosed with hepatocellular carcinoma (HCC) seek a satisfactory prognosis. However, most HCC patients present a risk of recurrence, thus highlighting the lack...
Patients diagnosed with hepatocellular carcinoma (HCC) seek a satisfactory prognosis. However, most HCC patients present a risk of recurrence, thus highlighting the lack of effectiveness of current treatments and the urgent need for improved treatment options. The purpose of this study was to identify new candidate factors in the STAT family, which is involved in hepatocellular carcinogenesis, and new targets for the treatment of HCC. Bioinformatics web resources, including Oncomine, Gene Expression Profiling Interactive Analysis (GEPIA), The Human Protein Atlas (HPA), Tumor Immune Estimation Resource (TIMER), and GSCALite, were used to identify candidate genes among the STAT family in HCC. STAT1 was significantly overexpressed in hepatocellular carcinoma. More meaningfully, the high STAT1 expression was significantly associated with poor prognosis. Therefore, STAT1 is expected to be a therapeutic target. The JAK2 inhibitor lestaurtinib was screened by the Genomics of Cancer Drug Sensitivity Project (GDSC) analysis. Pharmacological experiments showed that lestaurtinib has the ability to prevent cell migration and colony formation from single cells. We also found that STAT1 is involved in inflammatory responses and immune cell infiltration. Immune infiltration analysis revealed a strong association between STAT1 levels and immune cell abundance, immune biomarker levels, and immune checkpoints. This study suggests that STAT1 may be a key oncogene in hepatocellular carcinoma and provides evidence that the JAK2 inhibitor lestaurtinib is a potent antiproliferative agent that warrants further investigation as a targeted therapy for HCC.
PubMed: 35646925
DOI: 10.3389/fcell.2022.837428 -
International Journal of Molecular... May 2023Kidney renal clear cell carcinoma (KIRC) accounts for approximately 75% of all renal cancers. The prognosis for patients with metastatic KIRC is poor, with less than 10%...
Supervised Learning and Multi-Omics Integration Reveals Clinical Significance of Inner Membrane Mitochondrial Protein (IMMT) in Prognostic Prediction, Tumor Immune Microenvironment and Precision Medicine for Kidney Renal Clear Cell Carcinoma.
Kidney renal clear cell carcinoma (KIRC) accounts for approximately 75% of all renal cancers. The prognosis for patients with metastatic KIRC is poor, with less than 10% surviving five years after diagnosis. Inner membrane mitochondrial protein (IMMT) plays a crucial role in shaping the inner mitochondrial membrane (IMM), regulation of metabolism and innate immunity. However, the clinical relevance of IMMT in KIRC is not yet fully understood, and its role in shaping the tumor immune microenvironment (TIME) remains unclear. This study aimed to investigate the clinical significance of IMMT in KIRC using a combination of supervised learning and multi-omics integration. The supervised learning principle was applied to analyze a TCGA dataset, which was downloaded and split into training and test datasets. The training dataset was used to train the prediction model, while the test and the entire TCGA dataset were used to evaluate its performance. Based on the risk score, the cutoff between the low and high IMMT group was set at median value. A Kaplan-Meier curve, receiver operating characteristic (ROC) curve, principal component analysis (PCA) and Spearman's correlation were conducted to evaluate the prediction ability of the model. Gene Set Enrichment Analysis (GSEA) was used to investigate the critical biological pathways. Immunogenicity, immunological landscape and single-cell analysis were performed to examine the TIME. Databases including Gene Expression Omnibus (GEO), Human Protein Atlas (HPA) and Clinical Proteomic Tumor Analysis Consortium (CPTAC) were employed for inter-database verification. Pharmacogenetic prediction was analyzed via single-guide RNA (sgRNA)-based drug sensitivity screening using Q-omics v.1.30. Low expressions of IMMT in tumor predicted dismal prognosis in KIRC patients and correlated with KIRC progression. GSEA revealed that low expressions of IMMT were implicated in mitochondrial inhibition and angiogenetic activation. In addition, low IMMT expressions had associations with reduced immunogenicity and an immunosuppressive TIME. Inter-database verification corroborated the correlation between low IMMT expressions, KIRC tumors and the immunosuppressive TIME. Pharmacogenetic prediction identified lestaurtinib as a potent drug for KIRC in the context of low IMMT expressions. This study highlights the potential of IMMT as a novel biomarker, prognostic predictor and pharmacogenetic predictor to inform the development of more personalized and effective cancer treatments. Additionally, it provides important insights into the role of IMMT in the mechanism underlying mitochondrial activity and angiogenesis development in KIRC, which suggests IMMT as a promising target for the development of new therapies.
Topics: Humans; Precision Medicine; Prognosis; Clinical Relevance; Multiomics; Proteomics; Carcinoma, Renal Cell; Kidney Neoplasms; Mitochondrial Proteins; Supervised Machine Learning; Kidney; Tumor Microenvironment; Muscle Proteins
PubMed: 37240154
DOI: 10.3390/ijms24108807 -
Oncotarget 2015There is accumulating evidence that TrkA and its ligand Nerve Growth Factor (NGF) are involved in cancer development. Staurosporine derivatives such as K252a and...
There is accumulating evidence that TrkA and its ligand Nerve Growth Factor (NGF) are involved in cancer development. Staurosporine derivatives such as K252a and lestaurtinib have been developed to block TrkA kinase signaling, but no clinical trial has fully demonstrated their therapeutic efficacy. Therapeutic failures are likely due to the existence of intrinsic signaling pathways in cancer cells that impede or bypass the effects of TrkA tyrosine kinase inhibitors. To verify this hypothesis, we combined different approaches including mass spectrometry proteomics, co-immunoprecipitation and proximity ligation assays. We found that NGF treatment induced CD44 binding to TrkA at the plasma membrane and subsequent activation of the p115RhoGEF/RhoA/ROCK1 pathway to stimulate breast cancer cell invasion. The NGF-induced CD44 signaling was independent of TrkA kinase activity. Moreover, both TrkA tyrosine kinase inhibition with lestaurtinib and CD44 silencing with siRNA inhibited cell growth in vitro as well as tumor development in mouse xenograft model; combined treatment significantly enhanced the antineoplastic effects of either treatment alone. Altogether, our results demonstrate that NGF-induced tyrosine kinase independent TrkA signaling through CD44 was sufficient to maintain tumor aggressiveness. Our findings provide an alternative mechanism of cancer resistance to lestaurtinib and indicate that dual inhibition of CD44 and TrkA tyrosine kinase activity may represent a novel therapeutic strategy.
Topics: Animals; Biotinylation; Carbazoles; Cell Line, Tumor; Cell Membrane; Drug Resistance, Neoplasm; Female; Furans; Gene Silencing; Humans; Hyaluronan Receptors; Immunoprecipitation; Mass Spectrometry; Mice; Mice, SCID; Neoplasm Invasiveness; Neoplasm Transplantation; Nerve Growth Factor; Protein Binding; Proteomics; RNA, Small Interfering; Receptor, trkA; Signal Transduction
PubMed: 25840418
DOI: 10.18632/oncotarget.3227 -
Computational and Mathematical Methods... 2022Hypoxic pulmonary hypertension (HPH) is a fatal chronic pulmonary circulatory disease, characterized by hypoxic pulmonary vascular constriction and remodeling. Studies...
Hypoxic pulmonary hypertension (HPH) is a fatal chronic pulmonary circulatory disease, characterized by hypoxic pulmonary vascular constriction and remodeling. Studies performed to date have confirmed that endothelial dysfunction plays crucial roles in HPH, while the underlying mechanisms have not been fully revealed. The microarray dataset GSE11341 was downloaded from the Gene Expression Omnibus (GEO) database to identify differentially expressed genes (DEGs) between hypoxic and normoxic microvascular endothelial cell, followed by Gene Ontology (GO) annotation/Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Set Enrichment Analysis (GSEA) pathway enrichment analysis, and protein-protein interaction (PPI) network construction. Next, GSE160255 and RT-qPCR were used to validate hub genes. Meanwhile, GO/KEGG and GSEA were performed for each hub gene to uncover the potential mechanism. A nomogram based on hub genes was established. Furthermore, mRNA-miRNA network was predicted by miRNet, and the Connectivity Map (CMAP) database was in use to identify similarly acting therapeutic candidates. A total of 148 DEGs were screened in GSE11341, and three hub genes (, , and ) were determined and validated via GSE160255 and RT-qPCR. Abnormalities in the pathway of vascular smooth muscle contraction, lysosome, and glycolysis might play important roles in HPH pathogenesis. The hub gene-miRNA network showed that hsa-mir-24-3p, hsa-mir-124-3p, hsa-mir-195-5p, hsa-mir-146a-5p, hsa-mir-155-5p, and hsa-mir-23b-3p were associated with HPH. And on the basis of the identified hub genes, a practical nomogram is developed. To repurpose known and therapeutic drugs, three candidate compounds (procaterol, avanafil, and lestaurtinib) with a high level of confidence were obtained from the CMAP database. Taken together, the identification of these three hub genes, enrichment pathways, and potential therapeutic drugs might have important clinical implications for HPH diagnosis and treatment.
Topics: Humans; Hypertension, Pulmonary; Hypoxia; MicroRNAs; Computational Biology; Gene Ontology
PubMed: 36483920
DOI: 10.1155/2022/3677532