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

Chung, F.F.L. and Tan, P.F.T.M. and Raja, V.J. and Tan, B.S. and Lim, K.H. and Kam, T.S. and Hii, L.W. and Tan, S.H. and See, S.J. and Tan, Y.F. and Wong, L.Z. and Yam, W.K. and Mai, C.W. and Bradshaw, T.D. and Leong, C.O. (2017) Jerantinine A induces tumor-specific cell death through modulation of splicing factor 3b subunit 1 (SF3B1). Scientific Reports, 7 (1). p. 42504. ISSN 2045-2322, DOI

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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
Funders: Malaysia Ministry of Education Fundamental Research Grant Scheme (FRGS/2/2014/SKK02/IMU/03/3, WKY, LZW and COL; and FRGS/2/2014/SKK01/IMU/03/1, FFLC and SHT), Malaysia Ministry of Education High Impact Research Grant (HIR 005, KHL and TSK)
Uncontrolled Keywords: Jerantinine; Tumor-specific cell death; Splicing factor 3b subunit 1; SF3B1
Subjects: Q Science > QD Chemistry
R Medicine
Divisions: Faculty of Science > Department of Chemistry
Depositing User: Ms. Juhaida Abd Rahim
Date Deposited: 07 Sep 2018 03:40
Last Modified: 07 Sep 2018 03:40

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