Open AccessActivation of ASC induces apoptosis or necrosis, depending on the cell type, and causes tumor eradication
Author(s) -
Motani Kou,
Kawase Kouji,
Imamura Ryu,
Kinoshita Takeshi,
Kushiyama Hiroko,
Suda Takashi
Publication year - 2010
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2010.01610.x
Subject(s) - apoptosis , caspase , nlrc4 , programmed cell death , proteases , necrosis , cancer research , necroptosis , cancer cell , biology , cathepsin , calpain , microbiology and biotechnology , chemistry , cancer , caspase 1 , biochemistry , enzyme , genetics
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. ( Cancer Sci 2010)