USP17 is required for trafficking and oncogenic signaling of mutant EGFR in NSCLC cells.
Cell Commun Signal
; 16(1): 77, 2018 11 08.
Article
em En
| MEDLINE
| ID: mdl-30409180
ABSTRACT
BACKGROUND:
The deubiquitinase USP17 is overexpressed in NSCLC and has been shown to be required for the growth and motility of EGFR wild-type (WT) NSCLC cells. USP17 is also required for clathrin-mediated endocytosis of EGFR. Here, we examine the impact of USP17 depletion on the growth, as well as EGFR endocytosis and signaling, of EGFR mutant (MT) NSCLC cells. In particular, we examine NSCLC cells harboring an EGFR activating exon 19 deletion (HCC827), or both the L858R activating mutation and the T790M resistance gatekeeper mutation (H1975) which renders them resistant to EGFR tyrosine kinase inhibitors (TKIs).METHODS:
MTT, trypan blue and clonogenic assays, confocal microscopy, Western blotting and cell cycle analysis were performed.RESULTS:
USP17 depletion blocks the growth of EGFRMT NSCLC cells carrying either the EGFR exon 19 deletion, or L858R/T790M double mutation. In contrast to EGFRWT cells, USP17 depletion also triggers apoptosis of EGFRMT NSCLC cells. USP17 is required for clathrin-mediated endocytosis in these EGFRMT NSCLC cells, but it is not required for the internalization of the mutated EGFR receptors. Instead, USP17 depletion alters the localization of these receptors within the cell, and although it does not decrease basal EGFR activation, it potently reduces activation of Src, a key kinase in mutant EGFR-dependent tumorigenicity. Finally, we demonstrate that USP17 depletion can trigger apoptosis in EGFRWT NSCLC cells, when combined with the EGFR tyrosine kinase inhibitor (TKI) gefitinib.CONCLUSIONS:
Our data reveals that USP17 facilitates trafficking and oncogenic signaling of mutant EGFR and indicates targeting USP17 could represent a viable therapeutic strategy in NSCLC tumours carrying either an EGFR activating mutation, or a resistance gatekeeper mutation.Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Endopeptidases
/
Transdução de Sinais
/
Carcinoma Pulmonar de Células não Pequenas
/
Carcinogênese
/
Receptores ErbB
/
Neoplasias Pulmonares
/
Mutação
Limite:
Humans
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article