Abstract The Wilms' tumor 1 (WT1) gene is well known as a chameleon gene. It plays a role as a tumor suppressor in Wilms' tumor but also acts as an oncogene in other cancers. Previously, our group reported that a canonical AUG starting site for the WT1 protein (augWT1) acts as a tumor suppressor, whereas a CUG starting site for the WT1 protein (cugWT1) functions as an oncogene. In this study, we report an oncogenic role of cugWT1 in the AOM/DSS-induced colon cancer mouse model and in a urethane-induced lung cancer model in mice lacking cugWT1. Development of chemically-induced tumors was significantly depressed in cugWT1-deficient mice. Moreover, glycogen synthase kinase 3β promoted phosphorylation of cugWT1 at S64, resulting in ubiquitination and degradation of the cugWT1 associated with the F-box−/− WD repeat-containing protein 8. Overall, our findings suggest that inhibition of cugWT1 expression provides a potential candidate target for therapy. Significance: These findings demonstrate that CUG-translated WT1 plays an oncogenic role in vivo, and GSK3β-mediated phosphorylation of cugWT1 induces its ubiquitination and degradation in concert with FBXW8.
potentially contributing to abnormal autoimmune responses (1). Significant efforts are underway to discover specific and effective cGAS-STING inhibitors as researchers aim to blunt the cGAS-STING pathway in auto-immune disorders. A recent study showed that flavonoids are effective against the cGAS-STING pathway (6) and, in addition, flavonoids are known to have strong antiinflammatory activities (7). This research collection also highlights efficacy of Licorice extract and polysaccharide from Glycyrrhiza uralensis against cGAS-STING pathway (8,9).. Conversely, cGAS-STING agonists may offer therapeutic benefits; a recent study demonstrated that activating this pathway induces IFN-β and primes CD8+ T cells to target tumor cells, highlighting its potential in cancer immunotherapy (108). However, some research indicates that the cGAS-STING pathway may also facilitate tumorigenesis and metastasis (119).Chen et. al., offered a comprehensive review on the role of cGAS-STING in liver diseases such as viral hepatits B and hepatocellular carcinoma (12). During viral hepatitis, cGAS-STING signaling, and cytokine synthesis play a pivotal role in the antiviral-activity of hepatocytes. In hepatocellular carcinoma, the cGAS-STING pathway is activated by DNA damage, leading to IFN-1 release which in turn activates tumor-specific CD8 + T cell and helps induce systemic tumor immunity. Moreover, the authors suggest that the activation of the cGAS-IRF3 pathway is positively correlated with the severity of alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD).Another comprehensive review article by Ramos et. al. discusses the role of cGAS in various gastrointestinal (GI) diseases including inflammatory bowel disease (IBD) and in GI malignancy (13). The authors explain the contribution of cGAS-mediated autophagy activation on intestinal epithelial cell integrity and innate immunity responses. Interestingly, cGAS shows a contradictory role in GI-related cancers, showing both oncogenic and anti-oncogenic functions.Formatted: Font color: Red Formatted: Font color: Red Ramos et al. also discuss non-canonical activation of cGAS in various GI-related diseases (13).STING-independent activation of cGAS includes an interaction between cGAS and Beclin-1, autophagy activation and degradation of pathogenic DNA. On another note, cGAS mediated autophagy of micronuclei shows an interaction between cGAS and essential autophagy protein LC3. DNA damage in the nucleus can also trigger nuclear translocation of cGAS which inhibits homologous recombination of double strand breaks by interacting with PARP-1. The authors also summarize the potential antagonists and agonists used against cGAS in various cell lines and mouse models (13).In another cGAS-STING review, Colangelo et. al. explain the importance of cGAS-STING signaling in radiation therapy (14). The review gives an overview of the cGAS-STING pathway in tumor microenvironment after ionizing radiation exposure. DNA damage (nuclear or mitochondrial) from ionizing radiation releases to cytosol within a short period of time and activates cGAS-STING (14). The authors discuss the importance of immune cells in terms of STING activation, whether activated directly or by tumor-derived cGAMP (14)
The aim of the present study was to decipher the mechanism of glutathione‑S‑transferase Ω‑1 (GSTO1)‑induced drug resistance in colon cancer cells. Cisplatin is used widely as a therapeutic drug in cancer, but colon cancer is the most susceptible to acquired drug resistance. Autophagy is recognized as one of the contributors to drug resistance in cancers. Phase II detoxifying enzymes, such as GSTO1, serve important roles in autophagy‑apoptosis cross talk. The present study revealed a novel interaction between GSTO1 and TNFα‑induced protein 3/zinc‑finger protein A20 (TNFαIP3/A20) as a prime target for cisplatin sensitization in drug‑resistant cells. GSTO1 and ATP‑binding cassette subfamily B member 1 (ABCB1) were both expressed at higher levels in multidrug‑resistant (MDR) HCT‑116 cells compared with the wild‑type (WT) HCT‑116 cells, suggesting they may serve vital roles in multidrug resistance. MDR cells showed autophagy induction, which is dependent on calcium signaling‑dependent endoplasmic stress. In WT cells, the mitochondria‑dependent pathway leads to apoptosis, which was not observed in MDR cells. The MDR conditions were mimicked by transfecting WT cells with the GSTO1‑activation CRISPR plasmid, which induced autophagy. Similarly, MDR cells with GSTO1‑knockdown (KD) CRISPR/Cas9 transfection showed reduced autophagy with increased apoptosis. These data revealed a potentially important role of GSTO1 in drug resistance. A GSTO1 pull‑down assay detected TNFαIP3/A20 as a binding partner in MDR cells. The data suggested that the expression of TNFαIP3/A20 may be dependent on GSTO1 expression in MDR cells. Targeting either GSTO1 or TNFαIP3/A20 by CRISPR/Cas9 sensitized the MDR cells to cisplatin. GSTO1 and TNFαIP3/A20 dual‑KD cells were more sensitive to cisplatin compared with single‑gene KD cells. These data highlight the importance of the GSTO1‑TNFαIP3/A20 interaction during drug resistance.
Abstract Telomere maintenance is on the critical biological process in stem cell, aging, and cancer. Cells maintain telomere either by Telomerase (TERT) dependent pathway or by alternative lengthening of telomere (ALT) pathway. Here we report a link between Fyn kinase expression and telomere length. Fyn deficient mouse and mouse embryonic stem cells (mESC) maintain a stable telomere length through activation of ALT pathway. Fyn deficient mice are also resistant to the aging process as compared to wild type mice. We uncover a novel molecular mechanism of telomere maintenance. Menin, an essential component of an MLL/SET1 histone methyltransferase (HMT) complex that specifically methylates 'Lys-4' of histone H3 (H3K4), is a potential phosphorylation target of Fyn. Phosphorylation of Menin facilitates SUMOylation and binding to Telomerase RNA Component (TERC). The telomere dysfunction is one pivotal reason for many genetic disorders, including telomere related diseases like dyskeratosis congenita (DC). Currently, there are no curative therapies for these diseases of telomere dysfunction. We knockout Fyn gene from DC mice model and also used 4-Amino-5-(4-chlorophenyl)-7-(dimethyl ethyl) pyrazolo[3,4-d]pyrimidine (PP2), a selective inhibitor of Fyn kinase. Our results demonstrate that Fyn could be a therapeutic target in telomere related diseases. Knockout of Fyn or inhibition of Fyn by using inhibitor improves DC phenotype in mice like bone marrow failure. Human iPSC generated from DC patient's skin fibroblast shows higher expression of p-Menin and maintains a stable telomere length when we inhibited Fyn. Citation Format: Souren Paul, Thi My Le Le, Joohyun Ryu, Ki Beom Bae, Ann M. Bode, Zigang Dong. Fyn kinase negatively regulates telomere length in stem cells and cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5810.
The present study aimed at investigating the effects of essential oil of Trachyspermum ammi fruits, an oil-bearing plant of Apiaceae family, on human sperm viability and membrane integrity. Chemical compositions of the oil were analysed by GC-MS. Thirty compounds representing 91.39% of the total oil were identified. The viability and membrane integrity of human spermatozoa were assessed using minimum effective dose (MED) concentration (125 μg ml(-1)) of the oil. Sperm treated with essential oil showed a significant decrease (P < 0.05) in viability assessed by eosin-nigrosin and fluorescence dual staining. Moreover, the treated sperm also showed a significant loss (P < 0.05) of functional mitochondria and antioxidant enzyme, catalase (EC 1.11.1.6, CAT), when compared to control. The cholesterol:phospholipid ratio was also increased (P < 0.05) in treated sperm when compared to control, which is an indicator of loss of binding ability of human spermatozoa to the zona pellucida. The scanning electron microscopic studies demonstrated the loss of membrane integrity in essential oil-treated human spermatozoa, which showed vacuolation, swelling of acrosomal cap, detachment of head portion and tail coiling. Present observations indicate the spermicidal property of essential oil of T. ammi fruits, which could be helpful to develop medicinal preparations as a male contraceptive.
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