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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing
  • Animals
  • Cell Proliferation
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism*
  • Cell Transformation, Neoplastic / pathology
  • Cellular Senescence*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Heterogeneous-Nuclear Ribonucleoproteins / genetics
  • Heterogeneous-Nuclear Ribonucleoproteins / metabolism*
  • Humans
  • Inflammation / genetics
  • Inflammation / metabolism*
  • Inflammation / pathology
  • Inflammation / therapy
  • MCF-7 Cells
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neoplasms / genetics
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • Neoplasms / prevention & control
  • Paracrine Communication
  • Phenotype
  • Polypyrimidine Tract-Binding Protein / genetics
  • Polypyrimidine Tract-Binding Protein / metabolism*
  • RNA Interference
  • Signal Transduction
  • Tumor Burden
  • Vesicular Transport Proteins / genetics
  • Vesicular Transport Proteins / metabolism


  • Exoc7 protein, mouse
  • Heterogeneous-Nuclear Ribonucleoproteins
  • PTBP1 protein, human
  • Ptbp1 protein, mouse
  • Vesicular Transport Proteins
  • Polypyrimidine Tract-Binding Protein