Activation of ASC induces apoptosis or necrosis, depending on the cell type, and causes tumor eradication

Cancer Sci. 2010 Aug;101(8):1822-7. doi: 10.1111/j.1349-7006.2010.01610.x. Epub 2010 May 3.

Abstract

The adaptor protein ASC (also called TMS1) links certain NLR proteins (e.g., NLRC4, NLRP3) and caspases. It is involved in the chemosensitivity of tumor cells and inflammation. Here, we found that ASC activation using NLRC4 mimicry or an autoinflammatory disease-associated NLRP3 mutant induced necrosis in COLO205 colon adenocarcinoma cells, but induced caspase-8-dependent apoptosis in NUGC-4 stomach cancer cells. As the Fas ligand induced caspase-8-dependent apoptosis in COLO205 cells, caspase-8 was intact in this cell line. ASC-mediated necrosis was preceded by lysosomal leakage, and diminished by inhibitors for vacuolar H(+)-ATPase, cathepsins, and calpains but not by inhibitors for caspase-8, or aspartic proteases, suggesting that lysosomes and certain proteases were involved in this process. Finally, growing tumors of transplanted human cancer cells in nude mice were eradicated by the activation of endogenous ASC in the tumor cells, irrespective of the form of cell death. Thus, ASC mediates distinct forms of cell death in different cell types, and is a promising target for cancer therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylmuramyl-Alanyl-Isoglutamine / therapeutic use
  • Animals
  • Apoptosis*
  • CARD Signaling Adaptor Proteins
  • Caspase 8 / physiology
  • Cathepsins / physiology
  • Cell Line, Tumor
  • Cytoskeletal Proteins / physiology*
  • Female
  • Humans
  • Lysosomes / physiology
  • Mice
  • Mice, Inbred BALB C
  • Necrosis
  • Neoplasms / pathology
  • Neoplasms / therapy*

Substances

  • CARD Signaling Adaptor Proteins
  • Cytoskeletal Proteins
  • PYCARD protein, human
  • Acetylmuramyl-Alanyl-Isoglutamine
  • Cathepsins
  • Caspase 8