title: Jerantinine A induces tumor-specific cell death through modulation of splicing factor 3b subunit 1 (SF3B1).
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.
authors.affiliation: Center for Cancer and Stem Cell Research, International Medical University, Bukit Jalil, 57000 Kuala Lumpur, Malaysia.
authors.forename: Felicia Fei-Lei
authors.initials: FF
authors.lastname: Chung
authors.affiliation: School of Medicine, International Medical University, Bukit Jalil, 57000 Kuala Lumpur, Malaysia.
authors.forename: Perry Faith Tze Ming
authors.initials: PF
authors.lastname: Tan
authors.affiliation: Department of Biochemistry, Weill Cornell Medical College, New York, NY 10021, USA.
authors.forename: Vijay Joseph
authors.initials: VJ
authors.lastname: Raja
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.
authors.forename: Boon-Shing
authors.initials: BS
authors.lastname: Tan
authors.affiliation: School of Pharmacy, University of Nottingham Malaysia Campus, Jalan Broga, 43500 Semenyih, Selangor, Malaysia.
authors.forename: Kuan-Hon
authors.initials: KH
authors.lastname: Lim
authors.affiliation: Department of Chemistry, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia.
authors.forename: Toh-Seok
authors.initials: TS
authors.lastname: Kam
authors.affiliation: Center for Cancer and Stem Cell Research, International Medical University, Bukit Jalil, 57000 Kuala Lumpur, Malaysia.|School of Postgraduate Studies, International Medical University, Bukit Jalil, 57000 Kuala Lumpur, Malaysia.
authors.forename: Ling-Wei
authors.initials: LW
authors.lastname: Hii
authors.affiliation: Center for Cancer and Stem Cell Research, International Medical University, Bukit Jalil, 57000 Kuala Lumpur, Malaysia.|School of Postgraduate Studies, International Medical University, Bukit Jalil, 57000 Kuala Lumpur, Malaysia.
authors.forename: Si Hoey
authors.initials: SH
authors.lastname: Tan
authors.affiliation: Center for Cancer and Stem Cell Research, International Medical University, Bukit Jalil, 57000 Kuala Lumpur, Malaysia.
authors.forename: Sze-Jia
authors.initials: SJ
authors.lastname: See
authors.affiliation: Center for Cancer and Stem Cell Research, International Medical University, Bukit Jalil, 57000 Kuala Lumpur, Malaysia.|School of Postgraduate Studies, International Medical University, Bukit Jalil, 57000 Kuala Lumpur, Malaysia.
authors.forename: Yuen-Fen
authors.initials: YF
authors.lastname: Tan
authors.affiliation: Center for Cancer and Stem Cell Research, International Medical University, Bukit Jalil, 57000 Kuala Lumpur, Malaysia.|School of Postgraduate Studies, International Medical University, Bukit Jalil, 57000 Kuala Lumpur, Malaysia.
authors.forename: Li-Zhe
authors.initials: LZ
authors.lastname: Wong
authors.affiliation: School of Pharmacy, International Medical University, Bukit Jalil, 57000 Kuala Lumpur, Malaysia.
authors.forename: Wai Keat
authors.initials: WK
authors.lastname: Yam
authors.affiliation: School of Pharmacy, International Medical University, Bukit Jalil, 57000 Kuala Lumpur, Malaysia.
authors.forename: Chun Wai
authors.initials: CW
authors.lastname: Mai
authors.affiliation: School of Pharmacy, University of Nottingham, University Park, Nottingham NG7 2RD, UK.
authors.forename: Tracey D
authors.initials: TD
authors.lastname: Bradshaw
authors.affiliation: Center for Cancer and Stem Cell Research, International Medical University, Bukit Jalil, 57000 Kuala Lumpur, Malaysia.|School of Pharmacy, International Medical University, Bukit Jalil, 57000 Kuala Lumpur, Malaysia.
authors.forename: Chee-Onn
authors.initials: CO
authors.lastname: Leong
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms; D016923:Cell Death / Q000187:drug effects*; D045744:Cell Line, Tumor; D005260:Female; D055785:Gene Knockdown Techniques; D023281:Genomics / Q000379:methods; D006801:Humans; D026121:Indole Alkaloids / Q000494:pharmacology*; D061986:MCF-7 Cells; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D020543:Proteome; D040901:Proteomics / Q000379:methods; D012326:RNA Splicing / Q000187:drug effects; D000072260:RNA Splicing Factors / Q000235:genetics / Q000378:metabolism*; D017381:Spliceosomes / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D026121:Indole Alkaloids; D010750:Phosphoproteins; D020543:Proteome; D000072260:RNA Splicing Factors; C112491:SF3B1 protein, human; C000598423:jerantinine A