In silico identifying MET/FN1/TGFBI as molecular targets in drug-resistant head and neck cancer and preclinical repurposing sulfasalazine for enhanced therapeutic efficacy
Head and neck squamous cell carcinoma (HNSCC) is a highly aggressive cancer affecting over half a million people worldwide each year. Although recent FDA-approved treatments, like cetuximab, have shown promise, the five-year survival rate remains below 50 %. This underscores the need to identify mol...
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| Format: | Article |
| Language: | English |
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Elsevier
2024-03-01
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| Series: | Arabian Journal of Chemistry |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1878535223010237 |
| _version_ | 1797311603460276224 |
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| author | Ntlotlang Mokgautsi Alexander TH Wu Sheng-Yao Cheng Jih-Chin Lee Thomashire Anita George Jia-Hong Chen |
| author_facet | Ntlotlang Mokgautsi Alexander TH Wu Sheng-Yao Cheng Jih-Chin Lee Thomashire Anita George Jia-Hong Chen |
| author_sort | Ntlotlang Mokgautsi |
| collection | DOAJ |
| description | Head and neck squamous cell carcinoma (HNSCC) is a highly aggressive cancer affecting over half a million people worldwide each year. Although recent FDA-approved treatments, like cetuximab, have shown promise, the five-year survival rate remains below 50 %. This underscores the need to identify molecular signatures predicting clinical outcomes and potential therapeutic targets. Notably, the alteration of tyrosine-protein kinase Met (c-Met), a hepatocyte growth factor (HGF) receptor, stimulates tumor growth and metastasis across various cancers. However, its role and clinical implications in HNSCC remain unexplored. In HNSCC, MET's downstream signaling, mediated by phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt), is activated by fibronectin 1 (FN1), an extracellular matrix protein, fostering cancer progression. Additionally, FN1 and transforming growth factor-β (TGFB) are known to induce epithelial-mesenchymal transition in numerous cancers, leading to metastasis. Our computational analysis revealed significant upregulation of MET/FN1/TGFBI in HNSC at the mRNA level compared to normal samples. Given the immune system's pivotal role in HNSC progression, we analyzed the association of our target genes with immune infiltration. Our findings suggest a correlation between MET/FN1/TGFBI oncogenes and various stromal cells, highlighting their potential role in cancer recurrence and therapeutic resistance. We further explored the therapeutic potential of sulfasalazine, an anti-inflammatory drug. Molecular docking experiments revealed that sulfasalazine had a strong affinity for MET, FN1, and TGFBI, outperforming standard inhibitors in binding energy. These observations suggest sulfasalazine could be a promising MET/FN1/TGFBI gene signature inhibitor. Our study offers preclinical evidence supporting sulfasalazine as a standalone therapeutic agent and an adjunct to counteract cisplatin resistance in HNSC cells. |
| first_indexed | 2024-03-08T02:02:15Z |
| format | Article |
| id | doaj.art-b3ee116482564b0baee3bfe0fe3f4f50 |
| institution | Directory Open Access Journal |
| issn | 1878-5352 |
| language | English |
| last_indexed | 2024-03-08T02:02:15Z |
| publishDate | 2024-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Arabian Journal of Chemistry |
| spelling | doaj.art-b3ee116482564b0baee3bfe0fe3f4f502024-02-14T05:15:28ZengElsevierArabian Journal of Chemistry1878-53522024-03-01173105561In silico identifying MET/FN1/TGFBI as molecular targets in drug-resistant head and neck cancer and preclinical repurposing sulfasalazine for enhanced therapeutic efficacyNtlotlang Mokgautsi0Alexander TH Wu1Sheng-Yao Cheng2Jih-Chin Lee3Thomashire Anita George4Jia-Hong Chen5Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan, ROC; Graduate Institute for Cancer Biology & Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan, ROCThe PhD Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan, ROC; International PhD Program for Translational Science, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan, ROC; Clinical Research Center, Taipei Medical University Hospital, Taipei Medical University, Taipei 110, Taiwan, ROC; Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 110, Taiwan, ROCDepartment of Otolaryngology-Head and Neck Surgery, Tri-Service General Hospital, National Defense Medical Center, 325, Section 2, Chenggong Road, Taipei 114, Taiwan, ROCDepartment of Otolaryngology-Head and Neck Surgery, Tri-Service General Hospital, National Defense Medical Center, 325, Section 2, Chenggong Road, Taipei 114, Taiwan, ROCCollege of Medicine and Allied Health Sciences, University of Sierra Leone, Sierra LeoneDivision of Hematology and Oncology Medicine, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan, ROC; Corresponding author.Head and neck squamous cell carcinoma (HNSCC) is a highly aggressive cancer affecting over half a million people worldwide each year. Although recent FDA-approved treatments, like cetuximab, have shown promise, the five-year survival rate remains below 50 %. This underscores the need to identify molecular signatures predicting clinical outcomes and potential therapeutic targets. Notably, the alteration of tyrosine-protein kinase Met (c-Met), a hepatocyte growth factor (HGF) receptor, stimulates tumor growth and metastasis across various cancers. However, its role and clinical implications in HNSCC remain unexplored. In HNSCC, MET's downstream signaling, mediated by phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt), is activated by fibronectin 1 (FN1), an extracellular matrix protein, fostering cancer progression. Additionally, FN1 and transforming growth factor-β (TGFB) are known to induce epithelial-mesenchymal transition in numerous cancers, leading to metastasis. Our computational analysis revealed significant upregulation of MET/FN1/TGFBI in HNSC at the mRNA level compared to normal samples. Given the immune system's pivotal role in HNSC progression, we analyzed the association of our target genes with immune infiltration. Our findings suggest a correlation between MET/FN1/TGFBI oncogenes and various stromal cells, highlighting their potential role in cancer recurrence and therapeutic resistance. We further explored the therapeutic potential of sulfasalazine, an anti-inflammatory drug. Molecular docking experiments revealed that sulfasalazine had a strong affinity for MET, FN1, and TGFBI, outperforming standard inhibitors in binding energy. These observations suggest sulfasalazine could be a promising MET/FN1/TGFBI gene signature inhibitor. Our study offers preclinical evidence supporting sulfasalazine as a standalone therapeutic agent and an adjunct to counteract cisplatin resistance in HNSC cells.http://www.sciencedirect.com/science/article/pii/S1878535223010237Head and neck squamous cell carcinoma (HNSCC)Cisplatin resistancecancer-associated fibroblasts (CAF)Sulfasalazine |
| spellingShingle | Ntlotlang Mokgautsi Alexander TH Wu Sheng-Yao Cheng Jih-Chin Lee Thomashire Anita George Jia-Hong Chen In silico identifying MET/FN1/TGFBI as molecular targets in drug-resistant head and neck cancer and preclinical repurposing sulfasalazine for enhanced therapeutic efficacy Arabian Journal of Chemistry Head and neck squamous cell carcinoma (HNSCC) Cisplatin resistance cancer-associated fibroblasts (CAF) Sulfasalazine |
| title | In silico identifying MET/FN1/TGFBI as molecular targets in drug-resistant head and neck cancer and preclinical repurposing sulfasalazine for enhanced therapeutic efficacy |
| title_full | In silico identifying MET/FN1/TGFBI as molecular targets in drug-resistant head and neck cancer and preclinical repurposing sulfasalazine for enhanced therapeutic efficacy |
| title_fullStr | In silico identifying MET/FN1/TGFBI as molecular targets in drug-resistant head and neck cancer and preclinical repurposing sulfasalazine for enhanced therapeutic efficacy |
| title_full_unstemmed | In silico identifying MET/FN1/TGFBI as molecular targets in drug-resistant head and neck cancer and preclinical repurposing sulfasalazine for enhanced therapeutic efficacy |
| title_short | In silico identifying MET/FN1/TGFBI as molecular targets in drug-resistant head and neck cancer and preclinical repurposing sulfasalazine for enhanced therapeutic efficacy |
| title_sort | in silico identifying met fn1 tgfbi as molecular targets in drug resistant head and neck cancer and preclinical repurposing sulfasalazine for enhanced therapeutic efficacy |
| topic | Head and neck squamous cell carcinoma (HNSCC) Cisplatin resistance cancer-associated fibroblasts (CAF) Sulfasalazine |
| url | http://www.sciencedirect.com/science/article/pii/S1878535223010237 |
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