Abstract
Gamma-secretase, a unique aspartyl protease, is required for the regulated intramembrane proteolysis of Notch and APP, pathways that are implicated, respectively, in the pathogenesis of cancer and Alzheimer disease. However, the mechanism whereby reduction of gamma-secretase causes tumors such as squamous cell carcinoma (SCC) remains poorly understood. Here, we demonstrate that gamma-secretase functions in epithelia as a tumor suppressor in an enzyme activity-dependent manner. Notch signaling is down-regulated and epidermal growth factor receptor (EGFR) is activated in SCC caused by genetic reduction of gamma-secretase. Moreover, the level of EGFR is inversely correlated with the level of gamma-secretase in fibroblasts, suggesting that the up-regulation of EGFR stimulates hyperproliferation in epithelia of mice with genetic reduction of gamma-secretase. Supporting this notion is our finding that the proliferative response of fibroblasts lacking gamma-secretase activity is more sensitive when challenged by either EGF or an inhibitor of EGFR as ompared with wild type cells. Interestingly, the up-regulation of EGFR is independent of Notch signaling, suggesting that the EGFR pathway functions in parallel with Notch in the tumorigenesis of SCC. Collectively, our results establish a novel mechanism linking the EGFR pathway to the tumor suppressor role of gamma-secretase and that mice with genetic reduction of gamma-secretase represent an excellent rodent model for clarifying pathogenesis of SCC and for testing therapeutic strategy to ameliorate this type of human cancer.
Highlights
EXPERIMENTAL PROCEDURESAnimals and Cell Lines—Nctϩ/Ϫ mice were generated as described previously [12]
(A) peptides, aberrant accumulation of which is central to the pathogenesis of Alzheimer disease [1]
Because the skin tumors in Nctϩ/Ϫ mice resemble human head and neck squamous cell carcinoma (HNSCC), we examined pathways that are known to be activated in human HNSCC, including epidermal growth factor receptor (EGFR) pathways
Summary
Animals and Cell Lines—Nctϩ/Ϫ mice were generated as described previously [12]. Treatment of HEK293 Cell or Mice with ␥-Secretase Inhibitors—HEK293 cells were plated on 6-well plates the day before treatment. When the cells were ϳ50% confluent on the plates, the standard medium was replaced with medium containing different concentrations (0.5– 4 mM) of ␥-secretase inhibitor JC-22 [18]. The medium was changed every 24 h, and the cells were collected for analysis 48 h post-treatment. Some lesions gradually progressed to invasive SCC (Fig. 1, C and D) These SCCs of the head and neck areas in Nctϩ/Ϫ mice resembled HNSCC of human. The To clarify this issue, we treated mice with a ␥-secretase inhibicells were collected for analysis 48 h post-treatment
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