Project description:Targeting Dual-specificity Phosphatase 23 to Overcome Chemoresistance and Stem Cell-like Behavior in Non-small Cell Lung Cancer Cells
Project description:Chemoresistance poses a significant challenge in treating non-small cell lung cancer (NSCLC), often leading to poor outcomes. This resistance is closely linked to cancer stem cell (CSC)-like characteristics, including the ability to evade anoikis. In this study, we identified dual-specificity phosphatase 23 (DUSP23) as a key molecule involved in regulating CSC traits and chemoresistance. DUSP23 expression was significantly elevated in cell clusters grown under ultra-low adhesion (ULA) conditions that mimic CSC-promoting environments. Silencing DUSP23 reduced the formation of these clusters, suppressed the expression of the stemness markers SOX2, and enhanced anoikis sensitivity. Additionally, in cisplatin-resistant NSCLC cells, knockdown of DUSP23 decreased invasive behavior and induced apoptosis. These findings suggest that DUSP23 plays a pivotal role in maintaining CSC-like properties and chemoresistance by regulating SOX2. Targeting DUSP23 could offer a novel approach to overcome treatment resistance and improve outcomes for patients with NSCLC.
Project description:Mitogen-activated dual-specificity MAPK phosphatases are important negative regulators in the MAPK signalling pathways responsible for many essential processes in plants. In a screen for mutants with reduced organ size we have identified a mutation in the active site of the dual-specificity MAPK phosphatase INDOLE-3-BUTYRIC ACID-RESPONSE5 (IBR5) that we named tinkerbell (tink) due to its small size. Analysis of the tink mutant indicates that IBR5 acts as a novel regulator of organ size that changes the rate of growth in petals and leaves. Organ size and shape regulation by IBR5 acts independently of the KLU growth-regulatory pathway. Microarray analysis of tink/ibr5-6 mutants identified a likely role for this phosphatase in male gametophyte development. We show that IBR5 may influence the size and shape of petals through auxin and TCP growth regulatory pathways. 6 samples, three mutant replicates, three wild type replicates.
Project description:By using high-density DNA microarrays, we analyzed the gene-expression profile of Hodgkin's lymphoma cell line L-428 after knock-down of DUSP5 (dual specificity phosphatase 5)
Project description:By using high-density DNA microarrays, we analyzed the gene-expression profile of Hodgkin's lymphoma cell line L-428 after knock-down of DUSP5 (dual specificity phosphatase 5) RNA was extracted from established Hodgkin's lymphoma cell line L-428 and hybridized with Affymetrix HG_U133A microarrays.
Project description:<p>Overcoming resistance to chemotherapies remains a major unmet need for cancers such as triple negative breast cancer (TNBC). Therefore, mechanistic studies to provide insight for drug development are urgently needed to overcome TNBC therapy resistance. Recently, an important role of fatty acid β-Oxidation (FAO) in chemoresistance has been shown. But how FAO might mitigate tumor cell apoptosis by chemotherapy is unclear. Here, we show that elevated FAO activates STAT3 by acetylation via elevated acetyl-CoA. Acetylated STAT3 upregulates expression of long-chain acyl-CoA synthetase 4 (ACSL4), resulting in increased phospholipid synthesis. Elevating phospholipids in mitochondrial membranes leads to heightened mitochondrial integrity, which in turn overcomes chemotherapy-induced tumor cell apoptosis. Conversely, in both cultured tumor cells and xenograft tumors, enhanced cancer cell apoptosis by inhibiting ASCL4 or specifically targeting acetylated-STAT3 is associated with a reduction in phospholipids within mitochondrial membranes. This study demonstrates a critical mechanism underlying tumor cell chemoresistance.</p>
Project description:Mitogen-activated dual-specificity MAPK phosphatases are important negative regulators in the MAPK signalling pathways responsible for many essential processes in plants. In a screen for mutants with reduced organ size we have identified a mutation in the active site of the dual-specificity MAPK phosphatase INDOLE-3-BUTYRIC ACID-RESPONSE5 (IBR5) that we named tinkerbell (tink) due to its small size. Analysis of the tink mutant indicates that IBR5 acts as a novel regulator of organ size that changes the rate of growth in petals and leaves. Organ size and shape regulation by IBR5 acts independently of the KLU growth-regulatory pathway. Microarray analysis of tink/ibr5-6 mutants identified a likely role for this phosphatase in male gametophyte development. We show that IBR5 may influence the size and shape of petals through auxin and TCP growth regulatory pathways.
Project description:This study investigates the role of phosphoglycerate dehydrogenase (PHGDH) in 5-fluorouracil (5-FU) chemoresistance in colorectal cancer (CRC). The researchers discovered that PHGDH expression is highly variable in tumor tissues and patient-derived CRC organoids, with elevated PHGDH levels correlating with reduced sensitivity to 5-FU treatment. Through transcriptomic analysis, PHGDH was found to promote activation of the Hedgehog (HH) signaling pathway, which plays a key role in chemoresistance. PHGDH silencing reduces HH activation and increases sensitivity to 5-FU, while PHGDH overexpression has the opposite effect. Significantly, combined treatment with 5-FU and HH pathway inhibitors (JC19 or GANT61) synergistically enhances chemosensitivity in high-PHGDH expressing CRC cells, organoids, and xenograft models. This dual-targeting approach effectively limits tumor growth in mice. The findings establish PHGDH as a potential biomarker for predicting response to 5-FU-based chemotherapy and suggest that targeting the PHGDH-HH axis may represent a promising therapeutic strategy to overcome chemoresistance in CRC.
