Fasudil Increased the Sensitivity to Gefitinib in NSCLC by Decreasing Intracellular Lipid Accumulation
Tyrosine kinase inhibitors (TKIs) resistance is a challenge in patients with epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC). Here, we examined the effect of Fasudil in reversing TKIs resistance. The results of CCK8 assay, clone formation assay, cell cycle arrest an...
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| Format: | Article |
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MDPI AG
2022-09-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/14/19/4709 |
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| author | Tingting Liao Jingjing Deng Wenjuan Chen Juanjuan Xu Guanghai Yang Mei Zhou Zhilei Lv Sufei Wang Siwei Song Xueyun Tan Zhengrong Yin Yumei Li Yang Jin |
| author_facet | Tingting Liao Jingjing Deng Wenjuan Chen Juanjuan Xu Guanghai Yang Mei Zhou Zhilei Lv Sufei Wang Siwei Song Xueyun Tan Zhengrong Yin Yumei Li Yang Jin |
| author_sort | Tingting Liao |
| collection | DOAJ |
| description | Tyrosine kinase inhibitors (TKIs) resistance is a challenge in patients with epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC). Here, we examined the effect of Fasudil in reversing TKIs resistance. The results of CCK8 assay, clone formation assay, cell cycle arrest analysis, and apoptosis analysis show that Fasudil treatment effectively suppressed the growth and induced apoptosis of the EGFR-mutant NSCLC cells. Furthermore, Fasudil in combination with gefitinib showed a synergistic anti-tumor effect in gefitinib-resistant NSCLC cells. RNA-seq analysis and immunoblotting indicated that Fasudil treatment significantly inhibited intracellular lipid accumulation and EGFR/PI3K/AKT pathway activation. Mechanistic investigations showed that Fasudil regulated lipogenic gene expressions via AMPK signal pathway. In vivo, Fasudil and gefitinib co-administration significantly attenuated the growth of H1975 nude mouse xenograft models, suggesting that Fasudil treatment combined with gefitinib can be applied as a therapy for gefitinib-resistant NSCLC cells. |
| first_indexed | 2024-03-09T21:58:06Z |
| format | Article |
| id | doaj.art-de708a21d4cb43da922be340666d7560 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T21:58:06Z |
| publishDate | 2022-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-de708a21d4cb43da922be340666d75602023-11-23T19:55:21ZengMDPI AGCancers2072-66942022-09-011419470910.3390/cancers14194709Fasudil Increased the Sensitivity to Gefitinib in NSCLC by Decreasing Intracellular Lipid AccumulationTingting Liao0Jingjing Deng1Wenjuan Chen2Juanjuan Xu3Guanghai Yang4Mei Zhou5Zhilei Lv6Sufei Wang7Siwei Song8Xueyun Tan9Zhengrong Yin10Yumei Li11Yang Jin12NHC Key Laboratory of Pulmonary Diseases, Key Laboratory of Biological Targeted Therapy, Ministry of Education, Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, ChinaNHC Key Laboratory of Pulmonary Diseases, Key Laboratory of Biological Targeted Therapy, Ministry of Education, Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, ChinaNHC Key Laboratory of Pulmonary Diseases, Key Laboratory of Biological Targeted Therapy, Ministry of Education, Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, ChinaNHC Key Laboratory of Pulmonary Diseases, Key Laboratory of Biological Targeted Therapy, Ministry of Education, Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, ChinaDepartment of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, ChinaNHC Key Laboratory of Pulmonary Diseases, Key Laboratory of Biological Targeted Therapy, Ministry of Education, Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, ChinaNHC Key Laboratory of Pulmonary Diseases, Key Laboratory of Biological Targeted Therapy, Ministry of Education, Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, ChinaNHC Key Laboratory of Pulmonary Diseases, Key Laboratory of Biological Targeted Therapy, Ministry of Education, Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, ChinaNHC Key Laboratory of Pulmonary Diseases, Key Laboratory of Biological Targeted Therapy, Ministry of Education, Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, ChinaNHC Key Laboratory of Pulmonary Diseases, Key Laboratory of Biological Targeted Therapy, Ministry of Education, Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, ChinaNHC Key Laboratory of Pulmonary Diseases, Key Laboratory of Biological Targeted Therapy, Ministry of Education, Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, ChinaNHC Key Laboratory of Pulmonary Diseases, Key Laboratory of Biological Targeted Therapy, Ministry of Education, Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, ChinaNHC Key Laboratory of Pulmonary Diseases, Key Laboratory of Biological Targeted Therapy, Ministry of Education, Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, ChinaTyrosine kinase inhibitors (TKIs) resistance is a challenge in patients with epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC). Here, we examined the effect of Fasudil in reversing TKIs resistance. The results of CCK8 assay, clone formation assay, cell cycle arrest analysis, and apoptosis analysis show that Fasudil treatment effectively suppressed the growth and induced apoptosis of the EGFR-mutant NSCLC cells. Furthermore, Fasudil in combination with gefitinib showed a synergistic anti-tumor effect in gefitinib-resistant NSCLC cells. RNA-seq analysis and immunoblotting indicated that Fasudil treatment significantly inhibited intracellular lipid accumulation and EGFR/PI3K/AKT pathway activation. Mechanistic investigations showed that Fasudil regulated lipogenic gene expressions via AMPK signal pathway. In vivo, Fasudil and gefitinib co-administration significantly attenuated the growth of H1975 nude mouse xenograft models, suggesting that Fasudil treatment combined with gefitinib can be applied as a therapy for gefitinib-resistant NSCLC cells.https://www.mdpi.com/2072-6694/14/19/4709FasudilEGFRNSCLCgefitiniblipid metabolism |
| spellingShingle | Tingting Liao Jingjing Deng Wenjuan Chen Juanjuan Xu Guanghai Yang Mei Zhou Zhilei Lv Sufei Wang Siwei Song Xueyun Tan Zhengrong Yin Yumei Li Yang Jin Fasudil Increased the Sensitivity to Gefitinib in NSCLC by Decreasing Intracellular Lipid Accumulation Cancers Fasudil EGFR NSCLC gefitinib lipid metabolism |
| title | Fasudil Increased the Sensitivity to Gefitinib in NSCLC by Decreasing Intracellular Lipid Accumulation |
| title_full | Fasudil Increased the Sensitivity to Gefitinib in NSCLC by Decreasing Intracellular Lipid Accumulation |
| title_fullStr | Fasudil Increased the Sensitivity to Gefitinib in NSCLC by Decreasing Intracellular Lipid Accumulation |
| title_full_unstemmed | Fasudil Increased the Sensitivity to Gefitinib in NSCLC by Decreasing Intracellular Lipid Accumulation |
| title_short | Fasudil Increased the Sensitivity to Gefitinib in NSCLC by Decreasing Intracellular Lipid Accumulation |
| title_sort | fasudil increased the sensitivity to gefitinib in nsclc by decreasing intracellular lipid accumulation |
| topic | Fasudil EGFR NSCLC gefitinib lipid metabolism |
| url | https://www.mdpi.com/2072-6694/14/19/4709 |
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