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Objective: Pancreatic ductal adenocarcinoma (PDAC) still carries a dismal prognosis with an overall 5-year survival rate of 9%. Conventional combination chemotherapies are a clear advance in the treatment of PDAC; however, subtypes of the disease exist, which exhibit extensive resistance to such therapies. Genomic MYC amplifications represent a distinct subset of PDAC with an aggressive tumour biology. It is clear that hyperactivation of MYC generates dependencies that can be exploited therapeutically. The aim of the study was to find and to target MYC-associated dependencies.
Design: We analysed human PDAC gene expression datasets. Results were corroborated by the analysis of the small ubiquitin-like modifier (SUMO) pathway in a large PDAC cohort using immunohistochemistry. A SUMO inhibitor was used and characterised using human and murine two-dimensional, organoid and in vivo models of PDAC.
Results: We observed that MYC is connected to the SUMOylation machinery in PDAC. Components of the SUMO pathway characterise a PDAC subtype with a dismal prognosis and we provide evidence that hyperactivation of MYC is connected to an increased sensitivity to pharmacological SUMO inhibition.
Conclusion: SUMO inhibitor-based therapies should be further developed for an aggressive PDAC subtype.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7398468 | PMC |
http://dx.doi.org/10.1136/gutjnl-2018-317856 | DOI Listing |
Adv Sci (Weinh)
December 2024
Department of Anesthesiology and Pain Medicine, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Oxidative stress is believed to play critical pathophysiological roles in ischemic brain injury, and the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway is recognized as the most crucial endogenous antioxidant stress damage route. Some research have demonstrated that Nrf2 play critical roles in oxidative stress after ischemic stroke, but the underlying mechanism are not fully elucidated. This study reveals that Nrf2 is modified by SUMOylation and identifies Sentrin/SUMO-specific protease 6 (SENP6) as a negative regulator of Nrf2 SUMOylation.
View Article and Find Full Text PDFBiochem Biophys Res Commun
December 2024
Research Center for Molecular Mechanisms of Aging and Age-Related Diseases, Moscow Institute of Physics and Technology, Dolgoprudny, 141700, Russian Federation; Frank Laboratory of Neutron Physics, Joint Institute for Nuclear Research, Dubna, 141980, Russian Federation. Electronic address:
One of the promising drug delivery tools is ferritin, which features high stability at a wide range of conditions and protects cargo by its spherical protein shell. We studied the self-assembly into homoglobules of ferritin from H. pylori and a chimeric protein ferritin-SUMO.
View Article and Find Full Text PDFCancer Lett
December 2024
Shandong Provincial Key Laboratory of Precision Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, China. Electronic address:
Bone marrow stromal cells (BMSCs) are vital for preventing chemotherapy induced apoptosis of multiple myeloma (MM), but roles and machinery in other forms of cell death have not been well elucidated. Here, using an in vitro BMSC-MM interacting model, we observed BMSCs protected MM cells from labile iron pool (LIP) and reactive oxygen species (ROS) triggered ferroptosis by elevating glutathione peroxidase 4 (GPX4). Mechanistically, direct interaction with BMSCs upregulated the expression of SUMO-specific protease 3 (SENP3) in MM cells through CD40/CD40L signaling pathway, and SENP3 de-conjugated SUMO2 at lysine 75 residue to stabilize GPX4 protein, thereby consuming ROS to obviate ferroptosis in MM cells from the Vk∗MYC mouse model, as well as in CD138B220 cells separated from the Cd40l;Prx1 mice (CD40-CKO) and Sumo2 knock out (SUMO2-KO) mice.
View Article and Find Full Text PDFPLoS Pathog
December 2024
Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, India.
Candida glabrata is an opportunistic human pathogen, capable of causing severe systemic infections that are often resistant to standard antifungal treatments. To understand the importance of protein SUMOylation in the physiology and pathogenesis of C. glabrata, we earlier identified the components of SUMOylation pathway and demonstrated that the deSUMOylase CgUlp2 is essential for pathogenesis.
View Article and Find Full Text PDFCell Death Dis
December 2024
School of Biosciences, University of Sheffield, Firth Court, Western Bank, Sheffield, S10 2TN, UK.
SUMOylation, the covalent attachment of the small ubiquitin-like modifier (SUMO) to target proteins, and its reversal, deSUMOylation by SUMO proteases like Sentrin-specific proteases (SENPs), are crucial for initiating cellular responses to hypoxia. However, their roles in subsequent adaptation processes to hypoxia such as mitochondrial autophagy (mitophagy) remain unexplored. Here, we show that general SUMOylation, particularly SUMO2/3 modification, suppresses mitophagy under both normoxia and hypoxia.
View Article and Find Full Text PDFEnter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!