Subject(s)
Aurora Kinase B , Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , SMN Complex Proteins , Aurora Kinase B/genetics , Aurora Kinase B/metabolism , Carcinoma, Non-Small-Cell Lung/genetics , Gene Expression Regulation, Neoplastic , Humans , Lung Neoplasms/genetics , Proto-Oncogene Proteins c-myc/genetics , RNA, Messenger/genetics , SMN Complex Proteins/geneticsABSTRACT
The spindle assembly checkpoint (SAC) is a highly conserved monitoring system that ensures a fidelity of chromosome segregation during mitosis. Bub3, a mitotic Checkpoint Protein, is a member of the Bub protein family, and an important factor in the SAC. Abnormal expression of Bub3 results in mitotic defects, defective spindle gate function, chromosomal instability and the development of aneuploidy cells. Aneuploidy is a state of abnormal karyotype that has long been considered as a marker of tumorigenesis. Karyotypic heterogeneity in tumor cells, known as "chromosomal instability" (CIN), can be used to distinguish cancerous cells from their normal tissue counterpart. In this review, we summarize the expression and clinical significance of Bub3 in a variety of tumors and suggest that it has potential in the treatment of cancer.
Subject(s)
Cell Cycle Proteins , Neoplasms , Poly-ADP-Ribose Binding Proteins , Aneuploidy , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , Chromosomal Instability , Humans , Mitosis , Neoplasms/genetics , Neoplasms/metabolism , Poly-ADP-Ribose Binding Proteins/genetics , Poly-ADP-Ribose Binding Proteins/metabolism , Spindle Apparatus/metabolismSubject(s)
Carcinoma, Non-Small-Cell Lung/metabolism , Cell Cycle Proteins/metabolism , Lung Neoplasms/metabolism , MicroRNAs/metabolism , Neoplasm Proteins/metabolism , Neoplastic Stem Cells/metabolism , Nuclear Proteins/metabolism , Proteolysis , RNA, Neoplasm/metabolism , beta Catenin/metabolism , A549 Cells , Carcinoma, Non-Small-Cell Lung/genetics , Cell Cycle Proteins/genetics , Humans , Lung Neoplasms/genetics , MicroRNAs/genetics , Neoplasm Proteins/genetics , Nuclear Proteins/genetics , RNA, Neoplasm/genetics , beta Catenin/geneticsABSTRACT
Neural stem cells play pivotal roles during prenatal development and throughout life. Here, we report that Paired immunoglobulin-like receptor B (PirB) functions as a suppressor during brain neurogenesis in the adult mouse. PirB expression increased with age during development, and its deficiency promoted neural stem cell proliferation and differentiation in vivo and in vitro. Furthermore, we detected an increase in Type 1 neural stem cells in PirB-deficient mice compared to their wild-type littermates. PirB deficiency promoted stemness marker gene expression of Sox2 and KLF4 by activating Akt1 phosphorylation. These findings suggest that PirB inhibits the self-renewal and differentiation capacities of neural stem cells. Thus, PirB may have the potential to serve as a therapeutic target for treatment of reduced neurogenesis in adults due to aging or other pathological conditions.
Subject(s)
Hippocampus/cytology , Neural Stem Cells/metabolism , Receptors, Immunologic/metabolism , Aging/metabolism , Animals , Cell Differentiation , Cell Self Renewal , Kruppel-Like Factor 4 , Mice, Inbred C57BL , Neural Stem Cells/cytology , Phosphorylation , Proto-Oncogene Proteins c-akt/metabolism , Signal TransductionABSTRACT
Glioblastoma (GBM) is the most aggressive tumors of the central nervous system. Here, we report that SH3 binding glutamic acid-rich protein like 3 (SH3BGRL3) was extremely highly expressed in GBM and glioma stem cells. SH3BGRL3 high expression associates with worse survival of GBM patients. Functionally, Targeting SH3BGRL3 obviously impairs GSCs self-renewal in vitro. Most importantly, we first report that SH3BGRL3 is a direct transcriptional target gene of signal transducer and activator of transcription 3 (STAT3) and thereby activating STAT3 signaling in turn. Additionally, forced expression of the constitutively activated STAT3 (STAT3-C) rescued GSCs self-renewal inhibited by SH3BGRL3 silencing. Collectively, we first identified a critical positive feedback loop between SH3BGRL3 and STAT3, which facilitates the tumorigenic potential of GBM.
Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Carcinogenesis , Gene Expression Regulation, Neoplastic , Glioblastoma/genetics , Glioblastoma/pathology , STAT3 Transcription Factor/metabolism , Signal Transduction , Transcription, Genetic , Adaptor Proteins, Signal Transducing/biosynthesis , Adaptor Proteins, Signal Transducing/metabolism , Brain Neoplasms/diagnosis , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Carcinogenesis/genetics , Carcinogenesis/metabolism , Carcinogenesis/pathology , Cell Proliferation , Cell Self Renewal , Disease Progression , Glioblastoma/diagnosis , Humans , PrognosisABSTRACT
Triple-negative breast cancer (TNBC) has a poorer prognosis than other subtypes of breast cancer; however, it lacks effective targeted therapies clinically. In this study, we found FZU-0038-056, a novel compound derived from last-stage functionalization of tetrahydro-ß-carboline scaffold, showed the most potent anti-cancer activity against TNBC cells among the 42 synthesized derivatives. We found FZU-0038-056 significantly induces apoptosis in HCC1806 and HCC1937 TNBC cells. FZU-0038-056 reduces the expression levels of several anti-apoptosis proteins, including Bcl-2, Mcl-1 and XIAP. Furthermore, we found FZU-0038-056 induces apoptosis partially through inhibiting the expression of Bcl-2. Finally, we found FZU-0038-056 significantly suppresses HCC1806 xenograft tumor growth in nude mice without affecting their body weight. Therefore, FZU-0038-056 has the potential to be a new anticancer agent for treating human TNBC.
Subject(s)
Antineoplastic Agents/pharmacology , Carbolines/chemistry , Heterocyclic Compounds/pharmacology , Proto-Oncogene Proteins c-bcl-2/metabolism , Triple Negative Breast Neoplasms/drug therapy , Amines/chemistry , Animals , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Apoptosis Regulatory Proteins/metabolism , Cell Line, Tumor , Female , Heterocyclic Compounds/chemistry , Humans , Mice , Mice, Nude , Myeloid Cell Leukemia Sequence 1 Protein/metabolism , Pyrroles/chemistry , Quinolines/chemistry , Triple Negative Breast Neoplasms/genetics , X-Linked Inhibitor of Apoptosis Protein/metabolismABSTRACT
Purpose: Lung cancer is the leading cause of cancer related deaths worldwide. We have previously identified many differentially expressed genes (DEGs) from large scale pan-cancer dataset using the Cross-Value Association Analysis (CVAA) method. Here we focus on Progestin and AdipoQ Receptor 4 (PAQR4), a member of the progestin and adipoQ receptor (PAQR) family localized in the Golgi apparatus, to determine their clinical role and mechanism in the development of non-small cell lung cancer (NSCLC). Methods: The protein expression profile of PAQR4 was examined by IHC using tissue microarrays, and the effects of PAQR4 on cell proliferation, colony formation and xenograft tumor formation were tested in NSCLC cells. Real-time RT-PCR, co-immunoprecipitation (co-IP) and GST-pulldown assays were used to explore the mechanism of action of PAQR4. Results: We provided evidence showing that PAQR4 is increased in NSCLC cancer cell lines (A549, H1299, H1650, H1975, H358, GLC-82 and SPC-A1), and identified many mutations in PAQR4 in non-small cell lung cancer (NSCLC) tissues. We demonstrated that PAQR4 high expression correlates with a worse clinical outcome, and that its knockdown suppresses cell proliferation by inducing apoptosis. Importantly, overexpressed PAQR4 physically interacts with Nrf2 in NSCLC cells, blocking the interaction between Nrf2 and Keap1. Conclusion: Our results suggest that PAQR4 depletion enhances the sensitivity of cancerous cell to chemotherapy both in vitro and xenograft tumor formation in vivo, by promoting Nrf2 protein degradation through a Keap1-mediated ubiquitination process.
