Lysyl oxidase activity regulates oncogenic stress response and tumorigenesis

Cell Death Dis. 2013 Oct 10;4(10):e855. doi: 10.1038/cddis.2013.382.

Abstract

Cellular senescence, a stable proliferation arrest, is induced in response to various stresses. Oncogenic stress-induced senescence (OIS) results in blocked proliferation and constitutes a fail-safe program counteracting tumorigenesis. The events that enable a tumor in a benign senescent state to escape from OIS and become malignant are largely unknown. We show that lysyl oxidase activity contributes to the decision to maintain senescence. Indeed, in human epithelial cell the constitutive expression of the LOX or LOXL2 protein favored OIS escape, whereas inhibition of lysyl oxidase activity was found to stabilize OIS. The relevance of these in vitro observations is supported by in vivo findings: in a transgenic mouse model of aggressive pancreatic ductal adenocarcinoma (PDAC), increasing lysyl oxidase activity accelerates senescence escape, whereas inhibition of lysyl oxidase activity was found to stabilize senescence, delay tumorigenesis, and increase survival. Mechanistically, we show that lysyl oxidase activity favors the escape of senescence by regulating the focal-adhesion kinase. Altogether, our results demonstrate that lysyl oxidase activity participates in primary tumor growth by directly impacting the senescence stability.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / enzymology
  • Adenocarcinoma / pathology
  • Animals
  • Biocatalysis / drug effects
  • Carcinogenesis / metabolism
  • Carcinogenesis / pathology*
  • Carcinoma, Pancreatic Ductal / enzymology
  • Carcinoma, Pancreatic Ductal / pathology
  • Cellular Senescence / drug effects
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / pharmacology
  • Epithelial Cells / drug effects
  • Epithelial Cells / enzymology
  • Epithelial Cells / pathology
  • Focal Adhesion Protein-Tyrosine Kinases / metabolism
  • Humans
  • Mice
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Models, Biological
  • Neoplasms / enzymology*
  • Neoplasms / pathology*
  • Protein-Lysine 6-Oxidase / antagonists & inhibitors
  • Protein-Lysine 6-Oxidase / metabolism*
  • Stress, Physiological* / drug effects

Substances

  • Enzyme Inhibitors
  • Protein-Lysine 6-Oxidase
  • Focal Adhesion Protein-Tyrosine Kinases
  • Mitogen-Activated Protein Kinase Kinases