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Polyisoprenylated methylated protein methyl esterase overexpression and hyperactivity promotes lung cancer
Felix Amissah1, Randolph Duverna1, Byron J Aguilar1
1College of Pharmacy and Pharmaceutical Sciences, Florida A&M University Tallahassee, Florida 32307, USA.
Abstract:
The involvement of hyperactive polyisoprenylated proteins in cancers has stimulated the search for drugs to target and suppress their excessive activities. Polyisoprenylated methylated protein methyl esterase (PMPMEase) inhibition has been shown to modulate polyisoprenylated protein function. For PMPMEase inhibition to be effective against cancers, polyisoprenylated proteins, the signaling pathways they mediate and/or PMPMEase must be overexpressed, hyperactive and be involved in at least some cases of cancer. PMPMEase activity in lung cancer cells and its expression in lung cancer cells and cancer tissues were investigated. PMPMEase was found to be overexpressed and significantly more active in lung cancer A549 and H460 cells than in normal lung fibroblasts. In a tissue microarray study, PMPMEase immunoreactivity was found to be significantly higher in lung cancer tissues compared to the normal controls (p < 0.0001). The mean scores ± SEM were 118.8 ± 7.7 (normal), 232.1 ± 25.1 (small-cell lung carcinomas), 352.1 ± 9.4 (squamous cell carcinomas), 311.7 ± 9.8 (adenocarcinomas), 350.0 ± 24.2 (papillary adenocarcinomas), 334.7 ± 30.1 (adenosquamous carcinomas), 321.9 ± 39.7 (bronchioloalveolar carcinomas), and 331.3 ± 85.0 (large-cell carcinomas). Treatment of lung cancer cells with L-28, a specific PMPMEase inhibitor, resulted in concentration-dependent cell death (EC50 of 8.5 μM for A549 and 2.8 μM for H460 cells). PMPMEase inhibition disrupted actin filament assembly, significantly inhibited cell migration and altered the transcription of cancer-related genes. These results indicate that elevated PMPMEase activity spur cell growth and migration, implying the possible use of PMPMEase as a protein biomarker and drug target for lung cancer.
Insights
Polyisoprenylated methylated protein methyl esterase (PMPMEase) is overexpressed and highly active in lung cancer. Inhibiting PMPMEase with L-28 drug causes cancer cell death and reduces migration, suggesting its potential as a lung cancer biomarker and drug target.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Hyperactive polyisoprenylated proteins are implicated in cancer development.
- Polyisoprenylated methylated protein methyl esterase (PMPMEase) regulates polyisoprenylated protein function.
- Targeting PMPMEase is a potential therapeutic strategy for cancers where it is overexpressed or hyperactive.
Purpose of the Study:
- To investigate PMPMEase expression and activity in lung cancer.
- To evaluate the efficacy of PMPMEase inhibition as a potential lung cancer treatment.
- To explore PMPMEase as a potential diagnostic biomarker for lung cancer.
Main Methods:
- PMPMEase activity assays in lung cancer cell lines (A549, H460) and normal lung fibroblasts.
- Quantitative analysis of PMPMEase expression in lung cancer tissues using tissue microarrays.
- In vitro treatment of lung cancer cells with a specific PMPMEase inhibitor (L-28).
- Assessment of cell viability, migration, and gene transcription following PMPMEase inhibition.
Main Results:
- PMPMEase was significantly overexpressed and more active in lung cancer cells and tissues compared to normal controls.
- Treatment with L-28 induced concentration-dependent cell death in lung cancer cells.
- PMPMEase inhibition disrupted actin assembly, reduced cell migration, and altered cancer-related gene expression.
Conclusions:
- Elevated PMPMEase activity contributes to lung cancer cell growth and migration.
- PMPMEase is a promising therapeutic target for lung cancer.
- PMPMEase shows potential as a protein biomarker for lung cancer diagnosis and prognosis.
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