Purpose: Mevalonate pathway inhibitors are potentially useful chemotherapeutic agents showing growth inhibition and pro-apoptotic effects in cancer cells. The effects of statins and bisphosphonates on cancer growth are attributed to a reduction in protein isoprenylation. Post-translational modification and activation of GTPase binding Ras superfamily permit the recruitment of these signal proteins to membranes where they mediate the cancer phenotype. Here, the effects of three inhibitors of the mevalonate pathway and one specific inhibitor of sterol regulatory element-binding proteins were studied in both an ER-negative, Ras-inactive breast (MDA-MB-231) and lung adenocarcinoma (CaLu-1) cells in vitro.
Methods: Treated cells were subject to genome-wide gene expression profiling. A gene subset was established so that the epithelial to mesenchymal transition (EMT) could be observed and compared with signalling protein shifts.
Results: Within the subset, some genes normally up-regulated during EMT were asymmetrically reduced by a Δ-24 DHCR inhibitor in the lung cells. Signalling proteins associated with caveolae were down-regulated by this oxidoreductase inhibitor, while those associated with membrane rafts were up-regulated.
Conclusions: This study decouples isoprenylation effects from cholesterol events per se. The data support a hypothesis that caveolae are abolished by Δ-24 DHCR intervention and it is revealed that these microdomains are vital EMT signalling structures for lung cells but not ER- and Ras-negative breast cells. When signalling by extracellular signals is quenched by removal of the hydrophilic conduit provided by caveolae, the transcriptome responds by moving the cellular identity towards quiescence.
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http://dx.doi.org/10.1007/s00432-015-2074-3 | DOI Listing |
Metab Eng
January 2025
Biological Systems & Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA; Joint BioEnergy Institute, 5885 Hollis Street, Emeryville, CA, USA. Electronic address:
Prenol and isoprenol are promising advanced biofuels and serve as biosynthetic precursors for pharmaceuticals, fragrances, and other industrially relevant compounds. Despite engineering improvements that circumvent intermediate cytotoxicity and lower energy barriers, achieving high titer 'mevalonate (MVA)-derived' prenol has remained elusive. Difficulty in selective prenol production stems from the necessary isomerization of isopentenyl diphosphate (IPP) to dimethylallyl diphosphate (DMAPP) as well as the intrinsic toxicity of these diphosphate precursors.
View Article and Find Full Text PDFInt J Mol Sci
January 2025
State Key Laboratory of Tropical Crop Breeding, Sanya Institute, Rubber Research Institute, Chinese Academy of Tropical Agricultural Sciences, Sanya 572025, China.
The biosynthesis of isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP), which are essential for sesquiterpenes and triterpenes, respectively, is primarily governed by the mevalonate pathway, wherein () plays a pivotal role. This study identified eight members of the FPS gene family in , designated -, through bioinformatics analysis, revealing their distribution across several chromosomes and a notable tandem gene cluster. The genes exhibited strong hydrophilic properties and key functional motifs crucial for enzyme activity.
View Article and Find Full Text PDFInt J Mol Sci
January 2025
State Key Laboratory of Tree Genetics and Breeding, Nanjing Forestry University, Nanjing 210037, China.
Terpenoids, abundant and structurally diverse secondary metabolites in plants, especially in conifer species, play crucial roles in the plant defense mechanism and plant growth and development. In , terpenoids' biosynthesis relies on both the mevalonate (MVA) pathway and the 2-methyl-D-erythritol-4-phosphate (MEP) pathway, with 1-hydroxy-2-methyl-2-(E)-butenyl-4-diphosphate synthase (HDS) catalyzing the sixth step of the MEP pathway. In this study, we cloned and conducted bioinformatics analysis of the gene from .
View Article and Find Full Text PDFBiomed Pharmacother
January 2025
Ph.D. Program in Medical Neuroscience, Taipei Medical University and National Health Research Institutes, Taipei 11031, Taiwan; TMU Research Center for Drug Discovery, Taipei Medical University, Taipei 11031, Taiwan; International Master Program in Medical Neuroscience, Taipei Medical University, New Taipei City 23564, Taiwan; TMU Research Center of Neuroscience, Taipei Medical University, Taipei 11031, Taiwan; Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung 80780, Taiwan. Electronic address:
Traumatic brain injury (TBI) constitutes a significant burden on global healthcare systems, especially affecting younger populations, where it is a leading cause of disability and mortality. Current treatments for TBI mainly focus on preventing further brain damage and controlling symptoms. However, despite these approaches, several clinical needs remain unmet.
View Article and Find Full Text PDFCell Rep Med
January 2025
Renji-Med-X Clinical Stem Cell Research Center, Renji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200127, China; Med-X Research Institute, Shanghai Jiao Tong University, Shanghai 200030, China. Electronic address:
The induction of immunogenic cell death (ICD) impedes tumor progression via both tumor cell-intrinsic and -extrinsic mechanisms, representing a robust therapeutic strategy. However, ICD-targeted therapy remains to be explored and optimized. Through kinome-wide CRISPR-Cas9 screen, NUAK family SNF1-like kinase 1 (NUAK1) is identified as a potential target.
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