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Spliceosome component SF3B1 as novel prognostic biomarker and therapeutic target for prostate cancer.
- Source :
-
Translational research : the journal of laboratory and clinical medicine [Transl Res] 2019 Oct; Vol. 212, pp. 89-103. Date of Electronic Publication: 2019 Jul 09. - Publication Year :
- 2019
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Abstract
- Prostate cancer (PCa) is one of the most common cancers types among men. Development and progression of PCa is associated with aberrant expression of oncogenic splicing-variants (eg, AR-v7), suggesting that dysregulation of the splicing process might represent a potential actionable target for PCa. Expression levels (mRNA and protein) of SF3B1, one of the main components of the splicing machinery, were analyzed in different cohorts of PCa patients (clinically localized [n = 84], highly aggressive PCa [n = 42], and TCGA dataset [n = 497]). Functional and mechanistic assays were performed in response to pladienolide-B in nontumor and tumor-derived prostate cells. Our results revealed that SF3B1 was overexpressed in PCa tissues and its levels were associated with clinically relevant PCa-aggressive features (eg, metastasis/AR-v7 expression). Moreover, inhibition of SF3B1 activity by pladienolide-B reduced functional parameters of aggressiveness (proliferation/migration/tumorspheres-formation/apoptosis) in PCa cell lines, irrespective of AR-v7 expression, and reduced viability of primary PCa cells. Antitumor actions of pladienolide-B involved: (1) inhibition of PI3K/AKT and JNK signaling pathways, (2) modulation of tumor markers and splicing variants (AR-v7/In1-ghrelin), and (3) regulation of key components of mRNA homeostasis-associated machineries (spliceosome/SURF/EJC). Altogether, our results demonstrated that SF3B1 is overexpressed and associated with malignant features in PCa, and its inhibition reduces PCa aggressiveness, suggesting that SF3B1 could represent a novel prognostic biomarker and a therapeutic target in PCa.<br /> (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Subjects :
- Aged
Cell Line, Tumor
Cell Proliferation
Cohort Studies
Drug Delivery Systems
Gene Expression Regulation, Neoplastic
Humans
Male
Middle Aged
Phosphoproteins genetics
Prognosis
Prostatic Neoplasms drug therapy
RNA Splicing Factors genetics
Spliceosomes chemistry
Antineoplastic Agents pharmacology
Biomarkers, Tumor blood
Phosphoproteins metabolism
Prostatic Neoplasms metabolism
RNA Splicing Factors metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1878-1810
- Volume :
- 212
- Database :
- MEDLINE
- Journal :
- Translational research : the journal of laboratory and clinical medicine
- Publication Type :
- Academic Journal
- Accession number :
- 31344348
- Full Text :
- https://doi.org/10.1016/j.trsl.2019.07.001