Alectinib and lorlatinib function by modulating EMT-related proteins and MMPs in NSCLC metastasis
Most advanced non-small cell lung cancer (NSCLC) patients are accompanied by brain metastasis which is the major cause of increased mortality. The fusion rearrangement of anaplastic lymphoma kinase (ALK) gene is an important feature of brain metastasis in lung cancer. The novel ALK inhibitors alect...
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| Format: | Article |
| Language: | English |
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Association of Basic Medical Sciences of Federation of Bosnia and Herzegovina
2021-06-01
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| Series: | Biomolecules & Biomedicine |
| Subjects: | |
| Online Access: | https://www.bjbms.org/ojs/index.php/bjbms/article/view/5066 |
| _version_ | 1797261319137656832 |
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| author | Xu Feng En-Shi Xu |
| author_facet | Xu Feng En-Shi Xu |
| author_sort | Xu Feng |
| collection | DOAJ |
| description |
Most advanced non-small cell lung cancer (NSCLC) patients are accompanied by brain metastasis which is the major cause of increased mortality. The fusion rearrangement of anaplastic lymphoma kinase (ALK) gene is an important feature of brain metastasis in lung cancer. The novel ALK inhibitors alectinib and lorlatinib are shown to be effective against NSCLC brain metastasis, while their underlying mechanism of action is unclear. Epithelial–mesenchymal transition (EMT) proteins and matrix metalloproteinases (MMPs) play important roles in brain metastasis by regulating the blood-brain barrier (BBB). To reveal the molecular function of alectinib and lorlatinib, we explored their effects on the cellular levels of EMT markers: VIM and FN1 and the matrix metalloproteinases MMP-9 and MMP-7. The mRNA and protein levels of VIM, FN1, MMP-9, and MMP-7 were elevated in H3122 cells. However, upon alectinib and lorlatinib treatment, the levels were significantly reduced. Similar results were obtained when these experiments were performed either in a dose-dependent or time-dependent manner. Furthermore, alectinib and lorlatinib also inhibited the cell viability and migration of H3122 cells. Interestingly, in comparison to individual drugs, the combination of alectinib and lorlatinib was found to be substantially more effective. Overall, these results suggest that alectinib and lorlatinib possibly function through the downregulation of MMPs and EMT in NSCLC metastasis.
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| first_indexed | 2024-04-24T23:39:19Z |
| format | Article |
| id | doaj.art-bf98d5c3a6384a2f87afc12f79786588 |
| institution | Directory Open Access Journal |
| issn | 2831-0896 2831-090X |
| language | English |
| last_indexed | 2024-04-24T23:39:19Z |
| publishDate | 2021-06-01 |
| publisher | Association of Basic Medical Sciences of Federation of Bosnia and Herzegovina |
| record_format | Article |
| series | Biomolecules & Biomedicine |
| spelling | doaj.art-bf98d5c3a6384a2f87afc12f797865882024-03-15T13:44:14ZengAssociation of Basic Medical Sciences of Federation of Bosnia and HerzegovinaBiomolecules & Biomedicine2831-08962831-090X2021-06-0121310.17305/bjbms.2020.5066Alectinib and lorlatinib function by modulating EMT-related proteins and MMPs in NSCLC metastasisXu Feng0En-Shi Xu1https://orcid.org/0000-0003-0385-2885Department of Neurosurgery, The First Affiliated Hospital of Jinzhou Medical University 2 Section 5, Liaoning, ChinaDepartment of General Surgery, The First Affiliated Hospital of Jinzhou Medical University 2 Section 5, Liaoning, China Most advanced non-small cell lung cancer (NSCLC) patients are accompanied by brain metastasis which is the major cause of increased mortality. The fusion rearrangement of anaplastic lymphoma kinase (ALK) gene is an important feature of brain metastasis in lung cancer. The novel ALK inhibitors alectinib and lorlatinib are shown to be effective against NSCLC brain metastasis, while their underlying mechanism of action is unclear. Epithelial–mesenchymal transition (EMT) proteins and matrix metalloproteinases (MMPs) play important roles in brain metastasis by regulating the blood-brain barrier (BBB). To reveal the molecular function of alectinib and lorlatinib, we explored their effects on the cellular levels of EMT markers: VIM and FN1 and the matrix metalloproteinases MMP-9 and MMP-7. The mRNA and protein levels of VIM, FN1, MMP-9, and MMP-7 were elevated in H3122 cells. However, upon alectinib and lorlatinib treatment, the levels were significantly reduced. Similar results were obtained when these experiments were performed either in a dose-dependent or time-dependent manner. Furthermore, alectinib and lorlatinib also inhibited the cell viability and migration of H3122 cells. Interestingly, in comparison to individual drugs, the combination of alectinib and lorlatinib was found to be substantially more effective. Overall, these results suggest that alectinib and lorlatinib possibly function through the downregulation of MMPs and EMT in NSCLC metastasis. https://www.bjbms.org/ojs/index.php/bjbms/article/view/5066ALKalectiniblorlatinibVIMFN1MMPs |
| spellingShingle | Xu Feng En-Shi Xu Alectinib and lorlatinib function by modulating EMT-related proteins and MMPs in NSCLC metastasis Biomolecules & Biomedicine ALK alectinib lorlatinib VIM FN1 MMPs |
| title | Alectinib and lorlatinib function by modulating EMT-related proteins and MMPs in NSCLC metastasis |
| title_full | Alectinib and lorlatinib function by modulating EMT-related proteins and MMPs in NSCLC metastasis |
| title_fullStr | Alectinib and lorlatinib function by modulating EMT-related proteins and MMPs in NSCLC metastasis |
| title_full_unstemmed | Alectinib and lorlatinib function by modulating EMT-related proteins and MMPs in NSCLC metastasis |
| title_short | Alectinib and lorlatinib function by modulating EMT-related proteins and MMPs in NSCLC metastasis |
| title_sort | alectinib and lorlatinib function by modulating emt related proteins and mmps in nsclc metastasis |
| topic | ALK alectinib lorlatinib VIM FN1 MMPs |
| url | https://www.bjbms.org/ojs/index.php/bjbms/article/view/5066 |
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