Functional-proteomics-based investigation of the cellular response to farnesyltransferase inhibition in lung cancer
Summary: Farnesylation is a lipid post-translational modification of proteins crucial for protein membrane anchoring and cellular signaling. Farnesyltransferase inhibitors (FTIs), such as tipifarnib, are being tested in cancer therapy. However, the full impact of FTIs on farnesylation substrates rem...
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Elsevier
2025-02-01
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| Series: | iScience |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004225001245 |
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| author | Yanbo Pan Olena Berkovska Soumitra Marathe Georgios Mermelekas Greta Gudoityte Amare D. Wolide Taner Arslan Brinton Seashore-Ludlow Janne Lehtiö Lukas M. Orre |
| author_facet | Yanbo Pan Olena Berkovska Soumitra Marathe Georgios Mermelekas Greta Gudoityte Amare D. Wolide Taner Arslan Brinton Seashore-Ludlow Janne Lehtiö Lukas M. Orre |
| author_sort | Yanbo Pan |
| collection | DOAJ |
| description | Summary: Farnesylation is a lipid post-translational modification of proteins crucial for protein membrane anchoring and cellular signaling. Farnesyltransferase inhibitors (FTIs), such as tipifarnib, are being tested in cancer therapy. However, the full impact of FTIs on farnesylation substrates remains poorly understood, thus limiting their use in precision medicine. In this study, we performed a global proteomics analysis to investigate farnesylation and the effects of tipifarnib in lung cancer cell lines. Using metabolic labeling and mass spectrometry, we identified farnesylated proteins and mapped their subcellular localization. We also analyzed tipifarnib-dependent protein relocalization and proteome-wide changes. Key findings include the potential therapeutic value of FTIs for NRAS-mutated melanoma and GNAQ/GNA11-mutated uveal melanoma by inhibiting INPP5A farnesylation. Additionally, we identified a synergistic drug combination involving tipifarnib and a ferroptosis inducer and discovered PTP4A1 as a regulator of interferon signaling. Our data, covering 15,080 proteins, offer valuable insights for future studies of farnesylation and FTIs. |
| format | Article |
| id | doaj-art-e7f1682257f34fddb35023437c26034d |
| institution | Kabale University |
| issn | 2589-0042 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj-art-e7f1682257f34fddb35023437c26034d2025-02-07T04:48:04ZengElsevieriScience2589-00422025-02-01282111864Functional-proteomics-based investigation of the cellular response to farnesyltransferase inhibition in lung cancerYanbo Pan0Olena Berkovska1Soumitra Marathe2Georgios Mermelekas3Greta Gudoityte4Amare D. Wolide5Taner Arslan6Brinton Seashore-Ludlow7Janne Lehtiö8Lukas M. Orre9SciLifeLab, Department of Oncology and Pathology, Karolinska Institutet, 17165 Solna, SwedenSciLifeLab, Department of Oncology and Pathology, Karolinska Institutet, 17165 Solna, SwedenSciLifeLab, Department of Oncology and Pathology, Karolinska Institutet, 17165 Solna, SwedenSciLifeLab, Department of Oncology and Pathology, Karolinska Institutet, 17165 Solna, SwedenSciLifeLab, Department of Oncology and Pathology, Karolinska Institutet, 17165 Solna, SwedenSciLifeLab, Department of Oncology and Pathology, Karolinska Institutet, 17165 Solna, SwedenSciLifeLab, Department of Oncology and Pathology, Karolinska Institutet, 17165 Solna, SwedenSciLifeLab, Department of Oncology and Pathology, Karolinska Institutet, 17165 Solna, SwedenSciLifeLab, Department of Oncology and Pathology, Karolinska Institutet, 17165 Solna, Sweden; Corresponding authorSciLifeLab, Department of Oncology and Pathology, Karolinska Institutet, 17165 Solna, Sweden; Corresponding authorSummary: Farnesylation is a lipid post-translational modification of proteins crucial for protein membrane anchoring and cellular signaling. Farnesyltransferase inhibitors (FTIs), such as tipifarnib, are being tested in cancer therapy. However, the full impact of FTIs on farnesylation substrates remains poorly understood, thus limiting their use in precision medicine. In this study, we performed a global proteomics analysis to investigate farnesylation and the effects of tipifarnib in lung cancer cell lines. Using metabolic labeling and mass spectrometry, we identified farnesylated proteins and mapped their subcellular localization. We also analyzed tipifarnib-dependent protein relocalization and proteome-wide changes. Key findings include the potential therapeutic value of FTIs for NRAS-mutated melanoma and GNAQ/GNA11-mutated uveal melanoma by inhibiting INPP5A farnesylation. Additionally, we identified a synergistic drug combination involving tipifarnib and a ferroptosis inducer and discovered PTP4A1 as a regulator of interferon signaling. Our data, covering 15,080 proteins, offer valuable insights for future studies of farnesylation and FTIs.http://www.sciencedirect.com/science/article/pii/S2589004225001245Cell biologyCancerProteomics |
| spellingShingle | Yanbo Pan Olena Berkovska Soumitra Marathe Georgios Mermelekas Greta Gudoityte Amare D. Wolide Taner Arslan Brinton Seashore-Ludlow Janne Lehtiö Lukas M. Orre Functional-proteomics-based investigation of the cellular response to farnesyltransferase inhibition in lung cancer iScience Cell biology Cancer Proteomics |
| title | Functional-proteomics-based investigation of the cellular response to farnesyltransferase inhibition in lung cancer |
| title_full | Functional-proteomics-based investigation of the cellular response to farnesyltransferase inhibition in lung cancer |
| title_fullStr | Functional-proteomics-based investigation of the cellular response to farnesyltransferase inhibition in lung cancer |
| title_full_unstemmed | Functional-proteomics-based investigation of the cellular response to farnesyltransferase inhibition in lung cancer |
| title_short | Functional-proteomics-based investigation of the cellular response to farnesyltransferase inhibition in lung cancer |
| title_sort | functional proteomics based investigation of the cellular response to farnesyltransferase inhibition in lung cancer |
| topic | Cell biology Cancer Proteomics |
| url | http://www.sciencedirect.com/science/article/pii/S2589004225001245 |
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