J Cancer Prev.  2015 Mar;20(1):57-63. 10.15430/JCP.2015.20.1.57.

Inhibition of Ubiquitin-specific Peptidase 8 Suppresses Growth of Gefitinib-resistant Non-small Cell Lung Cancer Cells by Inducing Apoptosis

• Jeong CH

• KMID: 2171318
• DOI: http://doi.org/10.15430/JCP.2015.20.1.57

Abstract

BACKGROUND
Therapeutic approach by treatment with epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) like gefitinib or erlotinib to non-small cell lung cancer (NSCLC) patients has been limited due to emergence of acquired drug resistance. Our study was aimed to investigate whether the inhibition of ubiquitin-specific peptidase 8 (USP8) could be an alternative strategy capable of overcoming acquired resistance to EGFR-TKIs for treatment of NSCLCs.
METHODS
The anticancer effect of USP8 inhibitor was determined by testing anchorage-dependent or independent growth of gefitinib-sensitive or resistant NSCLCs. The immunoprecipitation and western blotting were conducted to check molecular interaction and signaling pathway followed by USP8 inhibition.
RESULTS
Inhibition of USP8 induced overall degradation of oncogenic receptor tyrosine kinases including EGFR and Met, leading to a suppression of anchorage-dependent or independent cell growth of gefitinib-sensitive or resistant NSCLCs. Also, treatment with the USP8 inhibitor markedly induced apoptosis in HCC827GR cells. Notably, treatment with the USP8 inhibitor was more effective in suppressing cell growth and inducing apoptosis in gefitinib-resistant HCC827GR cells than that of gefitinib-sensitive HCC827 cells.
CONCLUSIONS
Inhibition of USP8 could be an effective strategy for overcoming gefitinib resistance in NSCLCs.

Keyword

USP8; Non-small cell lung cancer; Gefitinib; Apoptosis; Resistance

MeSH Terms

Apoptosis*
Blotting, Western
Carcinoma, Non-Small-Cell Lung*
Drug Resistance
Epidermal Growth Factor
Erlotinib Hydrochloride
Humans
Immunoprecipitation
Phosphotransferases
Tyrosine
Epidermal Growth Factor
Phosphotransferases
Tyrosine