Jerantinine A induces tumor-specific cell death through modulation of splicing factor 3b subunit 1 (SF3B1)
| Autor: | Felicia Fei-Lei Chung, Wai Keat Yam, Sze-Jia See, Chee-Onn Leong, Boon Shing Tan, Kuan-Hon Lim, Toh-Seok Kam, Yuen-Fen Tan, Si Hoey Tan, Ling-Wei Hii, Vijay J. Raja, Tracey D. Bradshaw, Chun-Wai Mai, Perry Faith Tze Ming Tan, Li-Zhe Wong |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
Proteomics
0301 basic medicine RNA Splicing Factors Programmed cell death Spliceosome Proteome RNA Splicing Splicing Factor 3B Subunit 1 Antineoplastic Agents Apoptosis Breast Neoplasms Biology Article Indole Alkaloids Small hairpin RNA 03 medical and health sciences Cell Line Tumor Humans Multidisciplinary Cell Death Genomics Phosphoproteins Molecular biology Cell biology 030104 developmental biology Cell culture Gene Knockdown Techniques RNA splicing MCF-7 Cells Spliceosomes Female Precursor mRNA |
| Zdroj: | Scientific Reports |
| ISSN: | 2045-2322 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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