Identification of NSP3 (SH2D3C) as a Prognostic Biomarker of Tumor Progression and Immune Evasion for Lung Cancer and Evaluation of Organosulfur Compounds from Allium sativum L. as Therapeutic Candidates

Yuan-Chieh Yeh; Bashir Lawal; Michael Hsiao; Tse-Hung Huang; Chi-Ying F Huang

doi:10.3390/biomedicines9111582

Identification of NSP3 (SH2D3C) as a Prognostic Biomarker of Tumor Progression and Immune Evasion for Lung Cancer and Evaluation of Organosulfur Compounds from Allium sativum L. as Therapeutic Candidates

Biomedicines. 2021 Oct 30;9(11):1582. doi: 10.3390/biomedicines9111582.

Authors

Yuan-Chieh Yeh^{1

2}, Bashir Lawal^{3

4}, Michael Hsiao⁵, Tse-Hung Huang^{2

6

7

8

9

10}, Chi-Ying F Huang^{1

11

12}

Affiliations

¹ Program in Molecular Medicine, College of Life Sciences, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan.
² Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Keelung 20401, Taiwan.
³ PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.
⁴ Graduate Institute of Cancer Biology & Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.
⁵ Genomics Research Center, Academia Sinica, Taipei 115201, Taiwan.
⁶ School of Traditional Chinese Medicine, Chang Gung University, Kweishan, Taoyuan 333, Taiwan.
⁷ School of Nursing, National Taipei University of Nursing and Health Sciences, Taipei 112, Taiwan.
⁸ Graduate Institute of Health Industry Technology, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan.
⁹ Research Center for Chinese Herbal Medicine, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan.
¹⁰ Department & Graduate Institute of Chemical Engineering & Graduate Institute of Biochemical Engineering, Ming Chi University of Technology, New Taipei City 243, Taiwan.
¹¹ Institute of Biopharmaceutical Sciences, College of Pharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan.
¹² Department of Biochemistry, School of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.

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.

Keywords: NSCLC; NSP3 (SH2D3C); dysfunctional T-cell phenotypes; immune infiltrations; in silico study; organosulfur compounds; pharmacokinetics; tumor microenvironment.

Grants and funding

MOST 109-2327-B-010-005/Ministry of Science and Technology