Molecular Pathways: Understanding and Targeting Mutant Spliceosomal Proteins

Yoshimi, Akihide; Abdel‐Wahab, Omar

doi:10.1158/1078-0432.ccr-16-0131

Cited by 33 publications

(23 citation statements)

References 69 publications

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“…Pathway analysis suggests that many metabolism-related biological processes, such as xenobiotics metabolism, were significantly downregulated in the hepatoma cell lines compared with human livers, an observation consistent with previous reports [13, 16, 38]. Spliceosome proteins were significantly upregulated in all three cell lines, which may reflect the cancerous natures of the cells [40, 41].…”

Section: Discussionsupporting

confidence: 89%

Comparison of protein expression between human livers and the hepatic cell lines HepG2, Hep3B, and Huh7 using SWATH and MRM-HR proteomics: Focusing on drug-metabolizing enzymes

Shi

Wang

Lyu

et al. 2018

Drug Metabolism and Pharmacokinetics

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Human hepatic cell lines are widely used as an in vitro model for the study of drug metabolism and liver toxicity. However, the validity of this model is still a subject of debate because the expressions of various proteins in the cell lines, including drug-metabolizing enzymes (DMEs), can differ significantly from those in human livers. In the present study, we first conducted an untargeted proteomics analysis of the microsomes of the cell lines HepG2, Hep3B, and Huh7, and compared them to human livers using a sequential window acquisition of all theoretical mass spectra (SWATH) method. Furthermore, high-resolution multiple reaction monitoring (MRM-HR), a targeted proteomic approach, was utilized to compare the expressions of pre-selected DMEs between human livers and the cell lines. In general, the SWATH quantifications were in good agreement with the MRM-HR analysis. Over 3000 protein groups were quantified in the cells and human livers, and the proteome profiles of human livers significantly differed from the cell lines. Among the 101 DMEs quantified with MRM-HR, most were expressed at substantially lower levels in the cell lines. Thus, appropriate caution must be exercised when using these cell lines for the study of hepatic drug metabolism and toxicity.

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Section: Discussionsupporting

confidence: 89%

Comparison of protein expression between human livers and the hepatic cell lines HepG2, Hep3B, and Huh7 using SWATH and MRM-HR proteomics: Focusing on drug-metabolizing enzymes

Shi

Wang

Lyu

et al. 2018

Drug Metabolism and Pharmacokinetics

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“…For simplicity, only Complex A is shown here.U1 snRNP binds to the 5`SS via base-pairing interactions between small nuclear RNA (snRNA) and pre-mRNA; auxiliary U2AF2 and U2AF1 factors bind to the Poly-Y tract and to the 3`SS respectively; U2 snRNP binds to the BPS and base-pairing interactions are stabilized by SF3b complex. SF3B1 and PHFA5 (SF3B14), in particular, make contact with the “invariant” adenine of the BPS (“ A ”), which initiates the first transesterification reaction [51] [52]. (D) Representative pictures of TMA cores (original magnification 20×) obtained from paraffin-embedded DMPM specimens.…”

Section: Resultsmentioning

confidence: 99%

Splicing modulation as novel therapeutic strategy against diffuse malignant peritoneal mesothelioma

et al. 2019

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IntroductionTherapeutic options for diffuse malignant peritoneal mesothelioma (DMPM) are limited to surgery and locoregional chemotherapy. Despite improvements in survival rates, patients eventually succumb to disease progression. We investigated splicing deregulation both as molecular prognostic factor and potential novel target in DMPM, while we tested modulators of SF3b complex for antitumor activity.MethodsTissue-microarrays of 64 DMPM specimens were subjected to immunohistochemical assessment of SF3B1 expression and correlation to clinical outcome. Two primary cell cultures were used for gene expression profiling and in vitro screening of SF3b modulators. Drug-induced splicing alterations affecting downstream cellular pathways were detected through RNA sequencing. Ultimately, we established bioluminescent orthotopic mouse models to test the efficacy of splicing modulation in vivo.ResultsSpliceosomal genes are differentially upregulated in DMPM cells compared to normal tissues and high expression of SF3B1 correlated with poor clinical outcome in univariate and multivariate analysis. SF3b modulators (Pladienolide-B, E7107, Meayamycin-B) showed potent cytotoxic activity in vitro with IC50 values in the low nanomolar range. Differential splicing analysis of Pladienolide-B-treated cells revealed abundant alterations of transcripts involved in cell cycle, apoptosis and other oncogenic pathways. This was validated by RT-PCR and functional assays. E7107 demonstrated remarkable in vivo antitumor efficacy, with significant improvement of survival rates compared to vehicle-treated controls.ConclusionsSF3B1 emerged as a novel potential prognostic factor in DMPM. Splicing modulators markedly impair cancer cell viability, resulting also in potent antitumor activity in vivo. Our data designate splicing as a promising therapeutic target in DMPM.

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“… 21 , 23 , 25 In addition, mutations in these cis -acting splice enhancer or silencer elements could largely affect alternative splicing. 26 …”

Section: Regulatory Splicing Components and Alternative Splicingmentioning

confidence: 99%

Alternative splicing and cancer: a systematic review

Zhang

Qian

et al. 2021

Sig Transduct Target Ther

254

158

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The abnormal regulation of alternative splicing is usually accompanied by the occurrence and development of tumors, which would produce multiple different isoforms and diversify protein expression. The aim of the present study was to conduct a systematic review in order to describe the regulatory mechanisms of alternative splicing, as well as its functions in tumor cells, from proliferation and apoptosis to invasion and metastasis, and from angiogenesis to metabolism. The abnormal splicing events contributed to tumor progression as oncogenic drivers and/or bystander factors. The alterations in splicing factors detected in tumors and other mis-splicing events (i.e., long non-coding and circular RNAs) in tumorigenesis were also included. The findings of recent therapeutic approaches targeting splicing catalysis and splicing regulatory proteins to modulate pathogenically spliced events (including tumor-specific neo-antigens for cancer immunotherapy) were introduced. The emerging RNA-based strategies for the treatment of cancer with abnormally alternative splicing isoforms were also discussed. However, further studies are still required to address the association between alternative splicing and cancer in more detail.

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Molecular Pathways: Understanding and Targeting Mutant Spliceosomal Proteins

Cited by 33 publications

References 69 publications

Comparison of protein expression between human livers and the hepatic cell lines HepG2, Hep3B, and Huh7 using SWATH and MRM-HR proteomics: Focusing on drug-metabolizing enzymes

Comparison of protein expression between human livers and the hepatic cell lines HepG2, Hep3B, and Huh7 using SWATH and MRM-HR proteomics: Focusing on drug-metabolizing enzymes

Splicing modulation as novel therapeutic strategy against diffuse malignant peritoneal mesothelioma

Alternative splicing and cancer: a systematic review

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