DUSP1 expression induced by HDAC1 inhibition mediates gefitinib sensitivity in non-small cell lung cancers
Journal
Clinical Cancer Research
Journal Volume
21
Journal Issue
2
Pages
428-438
Date Issued
2015
Author(s)
Abstract
Purpose: Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related death worldwide. Patients with NSCLC with EGFR-activating mutation benefit greatly by gefitinib, an EGFR tyrosine kinase inhibitor. However, acquired resistance limits its clinical use. Histone deacetylases (HDAC) are oncoproteins associated with cancer progression and drug resistance. Here, we disclosed that inhibition of HDAC1 induced protein phosphatase DUSP1 upregulation to overcome gefitinib-acquired resistance. Experimental Design: The effect of HDAC1 inhibition restored gefitinib sensitivity was assessed by in vitro MTT and apoptotic assays, and in vivo xenograft and orthotopic lung cancer mouse models. Protein phosphatase array was used to detect DUSP1 expression. Immunohistochemical staining and quantitative PCR were used to analyze DUSP1 expression in clinical NSCLC specimens. Results: Gefitinib-resistant NSCLC cells showed HDAC1 overexpression, and its knockdown sensitized resistant cells to gefitinib in vitro and in preclinical models through DUSP1 expression. Overexpression of DUSP1 in resistant cells restored gefitinib sensitivity by inhibiting EGFR signaling and inducing apoptosis, whereas its knockdown in sensitive cells conferred gefitinib resistance. A novel HAD Cinhibitor, WJ-26210-2, in combination with gefitinib upregulated DUSP1 expression to exert in vitro and in vivo synergistic effect on inactivation of EGFR signaling, growth inhibition, and apoptosis. Clinically, high DUSP1 level was correlated with delayed emergence of gefitinib-acquired resistance. Conclusions: Decreased DUSP1 might be a mechanism responsible for gefitinib resistance, and DUSP1 might be a biomarker for gefitinib efficacy. HDAC1 inhibition-induced DUSP1 upregulation could be a promising strategy to overcome gefitinibacquired resistance. ? 2015 American Association for Cancer Research.
SDGs
Other Subjects
BIM protein; epidermal growth factor receptor; gefitinib; histone deacetylase 1; histone deacetylase inhibitor; messenger RNA; mitogen activated protein kinase; mitogen activated protein kinase phosphatase 1; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase; procaspase 3; protein kinase B; protein mcl 1; unclassified drug; vorinostat; wj 26210 2; antineoplastic agent; DUSP1 protein, human; gefitinib; HDAC1 protein, human; histone deacetylase 1; histone deacetylase inhibitor; mitogen activated protein kinase phosphatase 1; quinazoline derivative; animal experiment; animal model; animal tissue; apoptosis; Article; cancer inhibition; cancer prognosis; cancer resistance; cancer survival; cell viability; clinical article; concentration response; controlled study; drug efficacy; drug potentiation; drug sensitivity; drug sensitization; enzyme activation; enzyme inhibition; experimental design; gene expression regulation; gene silencing; human; human cell; human tissue; IC50; immunohistochemistry; in vitro study; in vivo study; intracellular signaling; lung cancer cell line; molecular dynamics; mouse; MTT assay; non small cell lung cancer; nonhuman; outcome assessment; polymerase chain reaction; progression free survival; protein expression; protein phosphorylation; tumor xenograft; upregulation; animal; antagonists and inhibitors; Bagg albino mouse; Carcinoma, Non-Small-Cell Lung; drug effects; drug resistance; drug screening; enzymology; genetics; Lung Neoplasms; metabolism; nonobese diabetic mouse; nude mouse; SCID mouse; tumor cell line; Animals; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Drug Resistance, Neoplasm; Drug Synergism; Dual Specificity Phosphatase 1; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Histone Deacetylase 1; Histone Deacetylase Inhibitors; Humans; Inhibitory Concentration 50; Lung Neoplasms; Mice, Inbred BALB C; Mice, Inbred NOD; Mice, Nude; Mice, SCID; Quinazolines; Xenograft Model Antitumor Assays
Type
journal article