Open AccessCancer‐associated missense mutations of caspase‐8 activate nuclear factor‐κB signaling
Author(s) -
Ando Mizuo,
Kawazu Masahito,
Ueno Toshihide,
Fukumura Kazutaka,
Yamato Azusa,
Soda Manabu,
Yamashita Yoshihiro,
Choi Young L.,
Yamasoba Tatsuya,
Mano Hiroyuki
Publication year - 2013
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/cas.12191
Subject(s) - biology , carcinogenesis , missense mutation , cancer research , head and neck squamous cell carcinoma , cancer , mutant , mutation , point mutation , cancer cell , effector , signal transduction , wild type , microbiology and biotechnology , gene , genetics , head and neck cancer
Head and neck squamous cell carcinoma ( HNSCC ) is an aggressive cancer with a 5‐year survival rate of ~50%. With the use of a custom cDNA ‐capture system coupled with massively parallel sequencing, we have now investigated transforming mechanisms for this malignancy. The cDNA s of cancer‐related genes ( n = 906) were purified from a human HNSCC cell line (T3M‐1 Cl‐10) and subjected to high‐throughput resequencing, and the clinical relevance of non‐synonymous mutations thus identified was evaluated with luciferase‐based reporter assays. A CASP 8 (procaspase‐8) cDNA with a novel G‐to‐C point mutation that results in the substitution of alanine for glycine at codon 325 was identified, and the mutant protein, CASP 8 (G325A), was found to activate nuclear factor‐κB ( NF ‐κB) signaling to an extent far greater than that achieved with the wild‐type protein. Moreover, forced expression of wild‐type CASP 8 suppressed the growth of T3M‐1 Cl‐10 cells without notable effects on apoptosis. We further found that most CASP 8 mutations previously detected in various epithelial tumors also increase the ability of the protein to activate NF ‐κB signaling. Such NF ‐κB activation was shown to be mediated through the COOH ‐terminal region of the second death effector domain of CASP 8. Although CASP 8 mutations associated with cancer have been thought to promote tumorigenesis as a result of attenuation of the proapoptotic function of the protein, our results now show that most such mutations, including the novel G325A identified here, separately confer a gain of function with regard to activation of NF ‐κB signaling, indicating another role of CASP8 in the transformation of human malignancies including HNSCC .