Cancer‐associated missense mutations of caspase‐8 activate nuclear factor‐κB signaling. Issue 8 (7th June 2013)

• Record Type: Journal Article
• Authors: Ando, Mizuo; Kawazu, Masahito; Ueno, Toshihide; Fukumura, Kazutaka; Yamato, Azusa; Soda, Manabu; Yamashita, Yoshihiro; Choi, Young L.; Yamasoba, Tatsuya; Mano, Hiroyuki
• Is Part Of: Cancer science. Volume 104:Issue 8(2013:Aug.)
• Page Start: 1002
• Page End: 1008
• Publication Date: 2013-06-07
• Subjects: Cancer -- Periodicals; Neoplasms -- Periodicals; Research -- Periodicals; Electronic journals; 616.994005
• DOI: 10.1111/cas.12191
• Languages: English
• ISSNs: 1347-9032

Abstract

Abstract : 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 cDNAs 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 CASP8 (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, CASP8 (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 CASP8 suppressed the growth of T3M‐1 Cl‐10 cells without notable effects on apoptosis. We further found that most CASP8 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 CASP8. Although CASP8 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.