Inhibition of CDCP1 by 8‐isopentenylnaringenin synergizes with EGFR inhibitors in lung cancer treatment
CUB domain‐containing protein 1 (CDCP1) contributes to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) resistance by regulating EGFR signaling pathways and is a potential target in lung cancer treatment. This study aims to identify a CDCP1 reducer that synergistically improve...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2023-08-01
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| Series: | Molecular Oncology |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/1878-0261.13429 |
| _version_ | 1797755338418552832 |
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| author | Sze‐Ching Wong Chun‐Chieh Yeh Xun‐Yu Zhang Chih‐Ying Hsieh Chia‐Chien Lo Ting‐Ting Kuo Ching‐Chan Lin Chih‐Hua Chao Jing‐Pei Liu Ling‐Chu Chang Lu‐Hai Wang Yuh‐Pyng Sher |
| author_facet | Sze‐Ching Wong Chun‐Chieh Yeh Xun‐Yu Zhang Chih‐Ying Hsieh Chia‐Chien Lo Ting‐Ting Kuo Ching‐Chan Lin Chih‐Hua Chao Jing‐Pei Liu Ling‐Chu Chang Lu‐Hai Wang Yuh‐Pyng Sher |
| author_sort | Sze‐Ching Wong |
| collection | DOAJ |
| description | CUB domain‐containing protein 1 (CDCP1) contributes to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) resistance by regulating EGFR signaling pathways and is a potential target in lung cancer treatment. This study aims to identify a CDCP1 reducer that synergistically improves TKI treatment. Utilizing a high‐throughput drug screening system, a phytoestrogen 8‐isopentenylnaringenin (8PN) was identified. Upon 8PN treatment, CDCP1 protein levels and malignant features were reduced. 8PN exposure caused the accumulation of lung cancer cells in G0/G1 phase and increased the proportion of senescent cells. In EGFR TKI‐resistant lung cancer cells, the combination of 8PN and TKI synergistically reduced cell malignance, inhibited downstream EGFR pathway signaling, and exerted additive effects on cell death. Moreover, combination therapy effectively reduced tumor growth and enhanced tumor necrosis in tumor xenograft mice models. Mechanistically, 8PN increased interleukin (IL)6 and IL8 expression, induced neutrophil infiltration, and enhanced neutrophil‐mediated cytotoxicity to attenuate lung cancer cell growth. In conclusion, 8PN enhances the anticancer efficacy of EGFR TKI on lung cancer and triggers neutrophil‐dependent necrosis, highlighting the potential to overcome TKI resistance in lung cancer patients who have EGFR mutation. |
| first_indexed | 2024-03-12T17:46:23Z |
| format | Article |
| id | doaj.art-353ae90eeedf4b26a5791f7b425b5f6c |
| institution | Directory Open Access Journal |
| issn | 1574-7891 1878-0261 |
| language | English |
| last_indexed | 2024-03-12T17:46:23Z |
| publishDate | 2023-08-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj.art-353ae90eeedf4b26a5791f7b425b5f6c2023-08-03T16:44:15ZengWileyMolecular Oncology1574-78911878-02612023-08-011781648166510.1002/1878-0261.13429Inhibition of CDCP1 by 8‐isopentenylnaringenin synergizes with EGFR inhibitors in lung cancer treatmentSze‐Ching Wong0Chun‐Chieh Yeh1Xun‐Yu Zhang2Chih‐Ying Hsieh3Chia‐Chien Lo4Ting‐Ting Kuo5Ching‐Chan Lin6Chih‐Hua Chao7Jing‐Pei Liu8Ling‐Chu Chang9Lu‐Hai Wang10Yuh‐Pyng Sher11Graduate Institute of Biomedical Sciences China Medical University Taichung TaiwanDepartment of Medicine, School of Medicine China Medical University Taichung TaiwanGraduate Institute of Biomedical Sciences China Medical University Taichung TaiwanGraduate Institute of Biomedical Sciences China Medical University Taichung TaiwanCenter for Molecular Medicine China Medical University Hospital Taichung TaiwanChinese Medicine Research Center China Medical University Taichung TaiwanDivision of Hematology and Oncology China Medical University Hospital Taichung TaiwanSchool of Pharmacy China Medical University Taichung TaiwanGraduate Institute of Biomedical Sciences China Medical University Taichung TaiwanCenter for Molecular Medicine China Medical University Hospital Taichung TaiwanChinese Medicine Research Center China Medical University Taichung TaiwanGraduate Institute of Biomedical Sciences China Medical University Taichung TaiwanCUB domain‐containing protein 1 (CDCP1) contributes to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) resistance by regulating EGFR signaling pathways and is a potential target in lung cancer treatment. This study aims to identify a CDCP1 reducer that synergistically improves TKI treatment. Utilizing a high‐throughput drug screening system, a phytoestrogen 8‐isopentenylnaringenin (8PN) was identified. Upon 8PN treatment, CDCP1 protein levels and malignant features were reduced. 8PN exposure caused the accumulation of lung cancer cells in G0/G1 phase and increased the proportion of senescent cells. In EGFR TKI‐resistant lung cancer cells, the combination of 8PN and TKI synergistically reduced cell malignance, inhibited downstream EGFR pathway signaling, and exerted additive effects on cell death. Moreover, combination therapy effectively reduced tumor growth and enhanced tumor necrosis in tumor xenograft mice models. Mechanistically, 8PN increased interleukin (IL)6 and IL8 expression, induced neutrophil infiltration, and enhanced neutrophil‐mediated cytotoxicity to attenuate lung cancer cell growth. In conclusion, 8PN enhances the anticancer efficacy of EGFR TKI on lung cancer and triggers neutrophil‐dependent necrosis, highlighting the potential to overcome TKI resistance in lung cancer patients who have EGFR mutation.https://doi.org/10.1002/1878-0261.134298‐isopentenylnaringeninEGFR TKI acquired resistancelung adenocarcinomanecrosissynergistic effects |
| spellingShingle | Sze‐Ching Wong Chun‐Chieh Yeh Xun‐Yu Zhang Chih‐Ying Hsieh Chia‐Chien Lo Ting‐Ting Kuo Ching‐Chan Lin Chih‐Hua Chao Jing‐Pei Liu Ling‐Chu Chang Lu‐Hai Wang Yuh‐Pyng Sher Inhibition of CDCP1 by 8‐isopentenylnaringenin synergizes with EGFR inhibitors in lung cancer treatment Molecular Oncology 8‐isopentenylnaringenin EGFR TKI acquired resistance lung adenocarcinoma necrosis synergistic effects |
| title | Inhibition of CDCP1 by 8‐isopentenylnaringenin synergizes with EGFR inhibitors in lung cancer treatment |
| title_full | Inhibition of CDCP1 by 8‐isopentenylnaringenin synergizes with EGFR inhibitors in lung cancer treatment |
| title_fullStr | Inhibition of CDCP1 by 8‐isopentenylnaringenin synergizes with EGFR inhibitors in lung cancer treatment |
| title_full_unstemmed | Inhibition of CDCP1 by 8‐isopentenylnaringenin synergizes with EGFR inhibitors in lung cancer treatment |
| title_short | Inhibition of CDCP1 by 8‐isopentenylnaringenin synergizes with EGFR inhibitors in lung cancer treatment |
| title_sort | inhibition of cdcp1 by 8 isopentenylnaringenin synergizes with egfr inhibitors in lung cancer treatment |
| topic | 8‐isopentenylnaringenin EGFR TKI acquired resistance lung adenocarcinoma necrosis synergistic effects |
| url | https://doi.org/10.1002/1878-0261.13429 |
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