Jerantinine A induces tumor-specific cell death through modulation of splicing factor 3b subunit 1 (SF3B1)

Chung, Felicia Fei-Lei and Tan, Perry Faith Tze Ming and Raja, Vijay Joseph and Tan, Boon-Shing and Lim, Kuan-Hon and Kam, Toh-Seok and Hii, Ling-Wei and Tan, Si Hoey and See, Sze-Jia and Tan, Yuen-Fen and Wong, Li-Zhe and Yam, Wai Keat and Mai, Chun Wai and 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

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Abstract

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.

Item Type: Article
Schools/Departments: University of Nottingham, UK > Faculty of Science > School of Pharmacy
Identification Number: 10.1038/srep42504
Depositing User: Eprints, Support
Date Deposited: 08 Mar 2017 11:48
Last Modified: 08 Mar 2017 11:49
URI: http://eprints.nottingham.ac.uk/id/eprint/41150

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