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Cancer Cell. 2018 Jul 9;34(1):85-102.e9. doi: 10.1016/j.ccell.2018.06.007.

PTBP1-Mediated Alternative Splicing Regulates the Inflammatory Secretome and the Pro-tumorigenic Effects of Senescent Cells.

Author information

1
MRC London Institute of Medical Sciences (LMS), Du Cane Road, London W12 0NN, UK; Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, Du Cane Road, London W12 0NN, UK.
2
Department of Internal Medicine VIII, University Hospital Tübingen, Tübingen 72076, Germany; Department of Physiology I, Institute of Physiology, Eberhard Karls University Tübingen, Tübingen 72076, Germany.
3
Cancer Sciences Unit, Cancer Research UK Centre, University of Southampton, Somers Building, Southampton SO16 6YD, UK.
4
Division of Chronic Inflammation and Cancer, German Cancer Research Centre (DKFZ), Heidelberg 69121, Germany.
5
Preclinical Research Program, Vall d'Hebron Institute of Oncology (VHIO) and CIBERONC, Barcelona 08035, Spain.
6
Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
7
MRC London Institute of Medical Sciences (LMS), Du Cane Road, London W12 0NN, UK; Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, Du Cane Road, London W12 0NN, UK; Division of Chronic Inflammation and Cancer, German Cancer Research Centre (DKFZ), Heidelberg 69121, Germany.
8
Institute of High Performance Computing, A(∗)STAR, 1 Fusionopolis Way, #16-16 Connexis, Singapore 138632, Singapore; Bioinformatics Institute, A(∗)STAR, 30 Biopolis Street, #07-01 Matrix, Singapore 138671, Singapore.
9
Methyltransferases in Development and Disease Group, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A(∗)STAR), Singapore, Singapore.
10
Preclinical Research Program, Vall d'Hebron Institute of Oncology (VHIO) and CIBERONC, Barcelona 08035, Spain; Department of Biochemistry and Molecular Biology, Universitat Autónoma de Barcelona, Campus de la UAB, Bellaterra 08193, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona 08010, Spain.
11
Department of Internal Medicine VIII, University Hospital Tübingen, Tübingen 72076, Germany; Department of Physiology I, Institute of Physiology, Eberhard Karls University Tübingen, Tübingen 72076, Germany; Translational Gastrointestinal Oncology Group, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
12
MRC London Institute of Medical Sciences (LMS), Du Cane Road, London W12 0NN, UK; Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, Du Cane Road, London W12 0NN, UK. Electronic address: jesus.gil@imperial.ac.uk.

Abstract

Oncogene-induced senescence is a potent tumor-suppressive response. Paradoxically, senescence also induces an inflammatory secretome that promotes carcinogenesis and age-related pathologies. Consequently, the senescence-associated secretory phenotype (SASP) is a potential therapeutic target. Here, we describe an RNAi screen for SASP regulators. We identified 50 druggable targets whose knockdown suppresses the inflammatory secretome and differentially affects other SASP components. Among the screen candidates was PTBP1. PTBP1 regulates the alternative splicing of genes involved in intracellular trafficking, such as EXOC7, to control the SASP. Inhibition of PTBP1 prevents the pro-tumorigenic effects of the SASP and impairs immune surveillance without increasing the risk of tumorigenesis. In conclusion, our study identifies SASP inhibition as a powerful and safe therapy against inflammation-driven cancer.

KEYWORDS:

EXOC7; Oncogene-induced senescence; PTBP1; RNAi screen; SASP; alternative splicing; senescence

PMID:
29990503
PMCID:
PMC6048363
DOI:
10.1016/j.ccell.2018.06.007
[Indexed for MEDLINE]
Free PMC Article

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