Mechanistic Insights of Anti-Immune Evasion by Nobiletin through Regulating miR-197/STAT3/PD-L1 Signaling in Non-Small Cell Lung Cancer (NSCLC) Cells
Tumor immune escape is a common process in the tumorigenesis of non-small cell lung cancer (NSCLC) cells where programmed death ligand-1 (PD-L1) expression, playing a vital role in immunosuppression activity. Additionally, epidermal growth factor receptor (EGFR) phosphorylation activates Janus kinas...
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2021-09-01
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| author | Nipin Sp Dong Young Kang Jin-Moo Lee Kyoung-Jin Jang |
| author_facet | Nipin Sp Dong Young Kang Jin-Moo Lee Kyoung-Jin Jang |
| author_sort | Nipin Sp |
| collection | DOAJ |
| description | Tumor immune escape is a common process in the tumorigenesis of non-small cell lung cancer (NSCLC) cells where programmed death ligand-1 (PD-L1) expression, playing a vital role in immunosuppression activity. Additionally, epidermal growth factor receptor (EGFR) phosphorylation activates Janus kinase-2 (JAK2) and signal transduction, thus activating transcription 3 (STAT3) to results in the regulation of PD-L1 expression. Chemotherapy with commercially available drugs against NSCLC has struggled in the prospect of adverse effects. Nobiletin is a natural flavonoid isolated from the citrus peel that exhibits anti-cancer activity. Here, we demonstrated the role of nobiletin in evasion of immunosuppression in NSCLC cells by Western blotting and real-time polymerase chain reaction methods for molecular signaling analysis supported by gene silencing and specific inhibitors. From the results, we found that nobiletin inhibited PD-L1 expression through EGFR/JAK2/STAT3 signaling. We also demonstrated that nobiletin exhibited p53-independent PD-L1 suppression, and that miR-197 regulates the expression of STAT3 and PD-L1, thereby enhancing anti-tumor immunity. Further, we evaluated the combination ability of nobiletin with an anti-PD-1 monoclonal antibody in NSCLC co-culture with peripheral blood mononuclear cells. Similarly, we found that nobiletin assisted the induction of PD-1/PD-L1 blockade, which is a key factor for the immune escape mechanism. Altogether, we propose nobiletin as a modulator of tumor microenvironment for cancer immunotherapy. |
| first_indexed | 2024-03-10T07:35:53Z |
| format | Article |
| id | doaj.art-924ea2eab1c64ff78ac8184a8375ad23 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T07:35:53Z |
| publishDate | 2021-09-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-924ea2eab1c64ff78ac8184a8375ad232023-11-22T13:28:25ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-09-012218984310.3390/ijms22189843Mechanistic Insights of Anti-Immune Evasion by Nobiletin through Regulating miR-197/STAT3/PD-L1 Signaling in Non-Small Cell Lung Cancer (NSCLC) CellsNipin Sp0Dong Young Kang1Jin-Moo Lee2Kyoung-Jin Jang3Department of Pathology, School of Medicine, Institute of Biomedical Science and Technology, Konkuk University, Chungju 27478, KoreaDepartment of Pathology, School of Medicine, Institute of Biomedical Science and Technology, Konkuk University, Chungju 27478, KoreaPharmacological Research Division, National Institute of Food and Drug Safety Evaluation, Osong Health Technology Administration Complex, Cheongju-si 28159, KoreaDepartment of Pathology, School of Medicine, Institute of Biomedical Science and Technology, Konkuk University, Chungju 27478, KoreaTumor immune escape is a common process in the tumorigenesis of non-small cell lung cancer (NSCLC) cells where programmed death ligand-1 (PD-L1) expression, playing a vital role in immunosuppression activity. Additionally, epidermal growth factor receptor (EGFR) phosphorylation activates Janus kinase-2 (JAK2) and signal transduction, thus activating transcription 3 (STAT3) to results in the regulation of PD-L1 expression. Chemotherapy with commercially available drugs against NSCLC has struggled in the prospect of adverse effects. Nobiletin is a natural flavonoid isolated from the citrus peel that exhibits anti-cancer activity. Here, we demonstrated the role of nobiletin in evasion of immunosuppression in NSCLC cells by Western blotting and real-time polymerase chain reaction methods for molecular signaling analysis supported by gene silencing and specific inhibitors. From the results, we found that nobiletin inhibited PD-L1 expression through EGFR/JAK2/STAT3 signaling. We also demonstrated that nobiletin exhibited p53-independent PD-L1 suppression, and that miR-197 regulates the expression of STAT3 and PD-L1, thereby enhancing anti-tumor immunity. Further, we evaluated the combination ability of nobiletin with an anti-PD-1 monoclonal antibody in NSCLC co-culture with peripheral blood mononuclear cells. Similarly, we found that nobiletin assisted the induction of PD-1/PD-L1 blockade, which is a key factor for the immune escape mechanism. Altogether, we propose nobiletin as a modulator of tumor microenvironment for cancer immunotherapy.https://www.mdpi.com/1422-0067/22/18/9843nobiletinNSCLCPD-L1EGFRJAK2/STAT3miR-197 |
| spellingShingle | Nipin Sp Dong Young Kang Jin-Moo Lee Kyoung-Jin Jang Mechanistic Insights of Anti-Immune Evasion by Nobiletin through Regulating miR-197/STAT3/PD-L1 Signaling in Non-Small Cell Lung Cancer (NSCLC) Cells International Journal of Molecular Sciences nobiletin NSCLC PD-L1 EGFR JAK2/STAT3 miR-197 |
| title | Mechanistic Insights of Anti-Immune Evasion by Nobiletin through Regulating miR-197/STAT3/PD-L1 Signaling in Non-Small Cell Lung Cancer (NSCLC) Cells |
| title_full | Mechanistic Insights of Anti-Immune Evasion by Nobiletin through Regulating miR-197/STAT3/PD-L1 Signaling in Non-Small Cell Lung Cancer (NSCLC) Cells |
| title_fullStr | Mechanistic Insights of Anti-Immune Evasion by Nobiletin through Regulating miR-197/STAT3/PD-L1 Signaling in Non-Small Cell Lung Cancer (NSCLC) Cells |
| title_full_unstemmed | Mechanistic Insights of Anti-Immune Evasion by Nobiletin through Regulating miR-197/STAT3/PD-L1 Signaling in Non-Small Cell Lung Cancer (NSCLC) Cells |
| title_short | Mechanistic Insights of Anti-Immune Evasion by Nobiletin through Regulating miR-197/STAT3/PD-L1 Signaling in Non-Small Cell Lung Cancer (NSCLC) Cells |
| title_sort | mechanistic insights of anti immune evasion by nobiletin through regulating mir 197 stat3 pd l1 signaling in non small cell lung cancer nsclc cells |
| topic | nobiletin NSCLC PD-L1 EGFR JAK2/STAT3 miR-197 |
| url | https://www.mdpi.com/1422-0067/22/18/9843 |
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