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Membrane‐tethered Notch1 exhibits oncogenic property via activation of EGFR–PI3K–AKT pathway in oral squamous cell carcinoma
Author(s) -
Zheng Yang,
Wang Zhao,
Xiong Xianbin,
Zhong Yi,
Zhang Wei,
Dong Yibo,
Li Jialiang,
Zhu Zaiou,
Zhang Wei,
Wu Heming,
Gu Wenyi,
Wu Yug,
Wang Xiang,
Song Xiaomeng
Publication year - 2019
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.27022
Subject(s) - pi3k/akt/mtor pathway , protein kinase b , microbiology and biotechnology , biology , signal transduction , cell growth , cancer research , epidermal growth factor receptor , notch signaling pathway , cell , chemistry , receptor , biochemistry
Notch proteins are highly conserved cell surface receptors which play essential roles in cellular differentiation, proliferation, and apoptotic events at all stages of development. Recently, NOTCH1 mutations have been extensively observed in oral squamous cell carcinoma (OSCC) and are hinted to be Notch1‐inactivating mutations. However, little is known about the biological effect of these reported mutations in OSCC. To mimic the inactivation of Notch1 due to inappropriate mutations and to determine the potential mechanisms, we utilized wild‐type Notch1 vectors (Notch1 WT ) or mutant Notch1 vectors (Notch1 V1754L ) to transfect into OSCC cell lines. Membrane‐tethered Notch1 induced by mutation was analyzed by immunofluorescence staining. γ‐Secretase inhibitor PF‐03084014 was utilized to determine the phenotype in the absence of endogenous Notch1 activation. Here we demonstrated that membrane‐tethered Notch1 inactivated the canonical Notch1 signaling and oncogenic phenotypes were identified by promoting cell proliferation and invasion and by inducing epithelial‐to‐mesenchymal transition in cells. The γ‐secretase inhibitor PF‐03084014 also showed distinct oncogenic property after treatment. Importantly, both membrane‐tethered Notch1 and PF‐03084014 inhibitor activated the epidermal growth factor receptor (EGFR)–phosphoinositide 3‐kinase (PI3K)–protein kinase B (AKT) signaling pathway, which has been confirmed as an overwhelming modulator in OSCC. This was the first time that we clearly simulated the mutated Notch1 activities and determined the oncogenic phenotypes of membrane‐tethered Notch1. Compared with wild‐type Notch1, membrane‐tethered Notch1 was strongly associated with activated EGFR–PI3K–AKT signaling pathway.