Abstract
The multi-domain non-structural protein 3 (NSP3) 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 NSP3 (SH2D3C) is associated with advanced stage and poor prognoses of lung cancer cohorts. Genetic alterations of NSP3 (SH2D3C) co-occurred inversely with Epidermal Growth Factor Receptor (EGFR) 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 NSP3 (SH2D3C) promotes tumor immune evasion via dysfunctional T-cell phenotypes and T-cell exclusion mechanisms in lung cancer patients. NSP3 (SH2D3C) 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 NSP3 (SH2D3C) target efficacy of six organosulfur small molecules from Allium sativum 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 NSP3 (SH2D3C)-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 NSP3 (SH2D3C) is unfavorable and hence less susceptible to NSP3 ligandability. In conclusion, our study revealed that NSP3 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 A. sativum have molecular properties to efficiently interact with the binding site of NSP3 and are currently under vigorous preclinical study in our laboratory.
Highlights
Lung cancer is the second most commonly diagnosed cancer, with an estimated2.2 million new cases (11.4%) worldwide, and remains the leading cause of cancer deaths, with an estimated 1.8 million deaths (18%) in 2020 [1]
Our differential expression profile of non-structural protein 3 (NSP3) (SH2D3C) between tumor and adjacent normal tissue revealed that NSP3 (SH2D3C) has deregulatory expression in tumor samples of The Cancer Genome Atlas (TCGA) cancer types (Figure 1A)
We found that cohorts with metastatic lung cancer exhibited higher NSP3 (SH2D3C) expression levels than the primary tumor (Figure 1C)
Summary
Lung cancer is the second most commonly diagnosed cancer, with an estimated2.2 million new cases (11.4%) worldwide, and remains the leading cause of cancer deaths, with an estimated 1.8 million deaths (18%) in 2020 [1]. With higher incidences and mortality rates in men than in women, the global burden of lung cancer is ranked first in men, whereas, in women, it ranks second behind breast cancer [1,2]. This pattern is largely attributed to air pollution and increased tobacco consumption [3,4]. NSCLC is further divided into three pathological subtypes of lung adenocarcinoma (LUAD), squamous cell carcinoma, and large-cell carcinoma, with LUAD being the most common subtype [7,8]. Despite advances in treatment strategies such as chemotherapy, immunotherapy, radiotherapy, and surgery, the prognosis of lung cancer is still disappointing with fewer than 20% of patients reaching an overall 5-year survival period [9,10]
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