AI Article Synopsis
- The study investigates how inhibiting enzymes in the mevalonate pathway can enhance the resilience of stromal cells to the cholesterol-dependent cytolysin, pyolysin (PLO), produced by Trueperella pyogenes.
- Depletion of cellular cholesterol using methyl-β-cyclodextrin showed increased cell resilience to PLO, and various pharmaceutical inhibitors were tested to reduce cholesterol levels.
- Among the enzymes studied, inhibiting FDFT1 was found to be the most effective, significantly lowering the negative impact of PLO on stromal cell viability.
Article Abstract
Animal health depends on the ability of immune cells to kill invading pathogens, and on the resilience of tissues to tolerate the presence of pathogens. Trueperella pyogenes causes tissue pathology in many mammals by secreting a cholesterol-dependent cytolysin, pyolysin (PLO), which targets stromal cells. Cellular cholesterol is derived from squalene, which is synthesized via the mevalonate pathway enzymes, including HMGCR, FDPS and FDFT1. The present study tested the hypothesis that inhibiting enzymes in the mevalonate pathway to reduce cellular cholesterol increases the resilience of stromal cells to PLO. We first verified that depleting cellular cholesterol with methyl-β-cyclodextrin increased the resilience of stromal cells to PLO. We then used siRNA to deplete mevalonate pathway enzyme gene expression, and used pharmaceutical inhibitors, atorvastatin, alendronate or zaragozic acid to inhibit the activity of HMGCR, FDPS and FDFT1, respectively. These approaches successfully reduced cellular cholesterol abundance, but mevalonate pathway enzymes did not affect cellular resilience equally. Inhibiting FDFT1 was most effective, with zaragozic acid reducing the impact of PLO on cell viability. The present study provides evidence that inhibiting FDFT1 increases stromal cell resilience to a cholesterol-dependent cytolysin.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5719056 | PMC |
| http://dx.doi.org/10.1038/s41598-017-17138-y | DOI Listing |
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Article Synopsis
- Insufficient interferon response in tumor cells limits the effectiveness of immune checkpoint blockade (ICB) therapy, particularly in anti-PD-1 treatment for microsatellite instability (MSI) colorectal cancer (CRC).
- Through screening, the study identified mevalonate kinase (MVK) as a key negative regulator of this interferon response in MSI CRC cells, where its genetic removal led to better immune cell infiltration and tumor growth suppression in mice.
- The research highlighted that lowered MVK expression in human tumor samples associates with improved responses to anti-PD-1 therapy, indicating that targeting MVK could enhance ICB therapy by boosting interferon signaling in MSI CRC patients.
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