Identification of <i>NSP3</i> (<i>SH2D3C</i>) as a Prognostic Biomarker of Tumor Progression and Immune Evasion for Lung Cancer and Evaluation of Organosulfur Compounds from <i>Allium sativum</i> L. as Therapeutic Candidates
The multi-domain non-structural protein 3 (<i>NSP3</i>) is an oncogenic molecule that has been concomitantly implicated in the progression of coronavirus infection. However, its oncological role in lung cancer and whether it plays a role in modulating the tumor immune microenvironment is...
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| Autores principales: | , , , , |
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| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
MDPI AG
2021
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| Materias: | |
| Acceso en línea: | https://doaj.org/article/c7fcc56987a24b0b9f044b50734d6b57 |
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| Sumario: | The multi-domain non-structural protein 3 (<i>NSP3</i>) is an oncogenic molecule that has been concomitantly implicated in the progression of coronavirus infection. However, its oncological role in lung cancer and whether it plays a role in modulating the tumor immune microenvironment is not properly understood. In the present in silico study, we demonstrated that <i>NSP3 (SH2D3C)</i> is associated with advanced stage and poor prognoses of lung cancer cohorts. Genetic alterations of <i>NSP3 (SH2D3C</i>) co-occurred inversely with Epidermal Growth Factor Receptor (<i>EGFR</i>) alterations and elicited its pathological role via modulation of various components of the immune and inflammatory pathways in lung cancer. Our correlation analysis suggested that <i>NSP3 (SH2D3C)</i> promotes tumor immune evasion via dysfunctional T-cell phenotypes and T-cell exclusion mechanisms in lung cancer patients. <i>NSP3 (SH2D3C)</i> demonstrated a high predictive value and association with therapy resistance in lung cancer, hence serving as an attractive target for therapy exploration. We evaluated the in silico drug-likeness and <i>NSP3 (SH2D3C)</i> target efficacy of six organosulfur small molecules from <i>Allium sativum</i> using a molecular docking study. We found that the six organosulfur compounds demonstrated selective cytotoxic potential against cancer cell lines and good predictions for ADMET properties, drug-likeness, and safety profile. E-ajoene, alliin, diallyl sulfide, 2-vinyl-4H-1,3-dithiin, allicin, and S-allyl-cysteine docked well into the <i>NSP3 (SH2D3C)</i>-binding cavity with binding affinities ranging from –4.3~–6.70 Ă and random forest (RF) scores ranging from 4.31~5.26 pKd. However, S-allyl-cysteine interaction with <i>NSP3 (SH2D3C)</i> is unfavorable and hence less susceptible to <i>NSP3</i> ligandability. In conclusion, our study revealed that <i>NSP3</i> is an important onco-immunological biomarker encompassing the tumor microenvironment, disease staging and prognosis in lung cancer and could serve as an attractive target for cancer therapy. The organosulfur compounds from <i>A. sativum</i> have molecular properties to efficiently interact with the binding site of <i>NSP3</i> and are currently under vigorous preclinical study in our laboratory. |
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