Jerantinine A induces tumor-specific cell death through modulation of splicing factor 3b subunit 1 (SF3B1)
Precursor mRNA (pre-mRNA) splicing is catalyzed by a large ribonucleoprotein complex known as the spliceosome. Numerous studies have indicated that aberrant splicing patterns or mutations in spliceosome components, including the splicing factor 3b subunit 1 (SF3B1), are associated with hallmark canc...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
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Nature Publishing Group
2017
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| Online Access: | https://eprints.nottingham.ac.uk/41150/ |
| _version_ | 1848796207773646848 |
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| author | Chung, Felicia Fei-Lei Tan, Perry Faith Tze Ming Raja, Vijay Joseph Tan, Boon-Shing Lim, Kuan-Hon Kam, Toh-Seok Hii, Ling-Wei Tan, Si Hoey See, Sze-Jia Tan, Yuen-Fen Wong, Li-Zhe Yam, Wai Keat Mai, Chun Wai Bradshaw, Tracey D. Leong, Chee-Onn |
| author_facet | Chung, Felicia Fei-Lei Tan, Perry Faith Tze Ming Raja, Vijay Joseph Tan, Boon-Shing Lim, Kuan-Hon Kam, Toh-Seok Hii, Ling-Wei Tan, Si Hoey See, Sze-Jia Tan, Yuen-Fen Wong, Li-Zhe Yam, Wai Keat Mai, Chun Wai Bradshaw, Tracey D. Leong, Chee-Onn |
| author_sort | Chung, Felicia Fei-Lei |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | Precursor mRNA (pre-mRNA) splicing is catalyzed by a large ribonucleoprotein complex known as the spliceosome. Numerous studies have indicated that aberrant splicing patterns or mutations in spliceosome components, including the splicing factor 3b subunit 1 (SF3B1), are associated with hallmark cancer phenotypes. This has led to the identification and development of small molecules with spliceosome-modulating activity as potential anticancer agents. Jerantinine A (JA) is a novel indole alkaloid which displays potent anti-proliferative activities against human cancer cell lines by inhibiting tubulin polymerization and inducing G2/M cell cycle arrest. Using a combined pooled-genome wide shRNA library screen and global proteomic profiling, we showed that JA targets the spliceosome by up-regulating SF3B1 and SF3B3 protein in breast cancer cells. Notably, JA induced significant tumor-specific cell death and a significant increase in unspliced pre-mRNAs. In contrast, depletion of endogenous SF3B1 abrogated the apoptotic effects, but not the G2/M cell cycle arrest induced by JA. Further analyses showed that JA stabilizes endogenous SF3B1 protein in breast cancer cells and induced dissociation of the protein from the nucleosome complex. Together, these results demonstrate that JA exerts its antitumor activity by targeting SF3B1 and SF3B3 in addition to its reported targeting of tubulin polymerization. |
| first_indexed | 2025-11-14T19:44:19Z |
| format | Article |
| id | nottingham-41150 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| last_indexed | 2025-11-14T19:44:19Z |
| publishDate | 2017 |
| publisher | Nature Publishing Group |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-411502020-05-04T18:34:38Z https://eprints.nottingham.ac.uk/41150/ Jerantinine A induces tumor-specific cell death through modulation of splicing factor 3b subunit 1 (SF3B1) Chung, Felicia Fei-Lei Tan, Perry Faith Tze Ming Raja, Vijay Joseph Tan, Boon-Shing Lim, Kuan-Hon Kam, Toh-Seok Hii, Ling-Wei Tan, Si Hoey See, Sze-Jia Tan, Yuen-Fen Wong, Li-Zhe Yam, Wai Keat Mai, Chun Wai Bradshaw, Tracey D. Leong, Chee-Onn Precursor mRNA (pre-mRNA) splicing is catalyzed by a large ribonucleoprotein complex known as the spliceosome. Numerous studies have indicated that aberrant splicing patterns or mutations in spliceosome components, including the splicing factor 3b subunit 1 (SF3B1), are associated with hallmark cancer phenotypes. This has led to the identification and development of small molecules with spliceosome-modulating activity as potential anticancer agents. Jerantinine A (JA) is a novel indole alkaloid which displays potent anti-proliferative activities against human cancer cell lines by inhibiting tubulin polymerization and inducing G2/M cell cycle arrest. Using a combined pooled-genome wide shRNA library screen and global proteomic profiling, we showed that JA targets the spliceosome by up-regulating SF3B1 and SF3B3 protein in breast cancer cells. Notably, JA induced significant tumor-specific cell death and a significant increase in unspliced pre-mRNAs. In contrast, depletion of endogenous SF3B1 abrogated the apoptotic effects, but not the G2/M cell cycle arrest induced by JA. Further analyses showed that JA stabilizes endogenous SF3B1 protein in breast cancer cells and induced dissociation of the protein from the nucleosome complex. Together, these results demonstrate that JA exerts its antitumor activity by targeting SF3B1 and SF3B3 in addition to its reported targeting of tubulin polymerization. Nature Publishing Group 2017-02-15 Article PeerReviewed Chung, Felicia Fei-Lei, Tan, Perry Faith Tze Ming, Raja, Vijay Joseph, Tan, Boon-Shing, Lim, Kuan-Hon, Kam, Toh-Seok, Hii, Ling-Wei, Tan, Si Hoey, See, Sze-Jia, Tan, Yuen-Fen, Wong, Li-Zhe, Yam, Wai Keat, Mai, Chun Wai, Bradshaw, Tracey D. and Leong, Chee-Onn (2017) Jerantinine A induces tumor-specific cell death through modulation of splicing factor 3b subunit 1 (SF3B1). Scientific Reports, 7 (42504). pp. 1-13. ISSN 2045-2322 http://www.nature.com/articles/srep42504 doi:10.1038/srep42504 doi:10.1038/srep42504 |
| spellingShingle | Chung, Felicia Fei-Lei Tan, Perry Faith Tze Ming Raja, Vijay Joseph Tan, Boon-Shing Lim, Kuan-Hon Kam, Toh-Seok Hii, Ling-Wei Tan, Si Hoey See, Sze-Jia Tan, Yuen-Fen Wong, Li-Zhe Yam, Wai Keat Mai, Chun Wai Bradshaw, Tracey D. Leong, Chee-Onn Jerantinine A induces tumor-specific cell death through modulation of splicing factor 3b subunit 1 (SF3B1) |
| title | Jerantinine A induces tumor-specific cell death through modulation of splicing factor 3b subunit 1 (SF3B1) |
| title_full | Jerantinine A induces tumor-specific cell death through modulation of splicing factor 3b subunit 1 (SF3B1) |
| title_fullStr | Jerantinine A induces tumor-specific cell death through modulation of splicing factor 3b subunit 1 (SF3B1) |
| title_full_unstemmed | Jerantinine A induces tumor-specific cell death through modulation of splicing factor 3b subunit 1 (SF3B1) |
| title_short | Jerantinine A induces tumor-specific cell death through modulation of splicing factor 3b subunit 1 (SF3B1) |
| title_sort | jerantinine a induces tumor-specific cell death through modulation of splicing factor 3b subunit 1 (sf3b1) |
| url | https://eprints.nottingham.ac.uk/41150/ https://eprints.nottingham.ac.uk/41150/ https://eprints.nottingham.ac.uk/41150/ |