DARPP-32 increases interactions between epidermal growth factor receptor and ERBB3 to promote tumor resistance to gefitinib.

Zhu S, Belkhiri A, El-Rifai W
Gastroenterology. 2011 141 (5): 1738-48.e1-2

PMID: 21741919 · PMCID: PMC3202055 · DOI:10.1053/j.gastro.2011.06.070

BACKGROUND & AIMS - Dopamine and adenosine 3',5'-cyclic monophosphate-regulated phosphoprotein, Mr 32000 (DARPP-32), is overexpressed during gastric carcinogenesis. Gastric tumors can become resistant to gefitinib, an inhibitor of the epidermal growth factor receptor (EGFR). We investigated the role of DARPP-32 in gastric tumor resistance to gefitinib.

METHODS - Cell survival was determined by clonogenic survival and ATP-Glo Viability Assays. Apoptosis was assessed by Annexin-V and immunoblot analyses. The association between DARPP-32 and EGFR was evaluated by immunofluorescence and co-immunoprecipitation assays. Findings were validated in mice with gastric xenograft tumors. DARPP-32 expression was reduced using small hairpin RNAs in the human gastric cancer cell lines SNU-16 and MKN-45 cells.

RESULTS - Overexpression of DARPP-32 in MKN-28 cells, which do not normally express DARPP-32, blocked gefitinib-induced apoptosis and increased the drug's IC(50) 10-fold, compared to that of control cells (P < .01). Reduced expression of DARPP-32 in SNU-16 cells increased the sensitivity to gefitinib (P < .01). DARPP-32 activated phosphatidylinositol-3-kinase-AKT signaling, increased stability of the EGFR, and suppressed EGF- or gefitinib-induced degradation of the EGFR. DARPP-32 colocalized with EGFR on the cell membrane in a complex with EGFR and the EGF receptor ERBB3. DARPP-32-mediated resistance to gefitinib resulted from increased phosphorylation of and interaction between EGFR and ERBB3, which led to phosphorylation of AKT (at serine 473). Knockdown of DARPP-32 in gastric cancer cells reduced the mean size of tumors in mice and increased their response to gefitinib.

CONCLUSIONS - DARPP-32 promotes resistance of gastric cancer cells to gefitinib by promoting interaction between EGFR and ERBB3 and activating phosphatidylinositol-3-kinase-AKT signaling.

Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.

MeSH Terms (20)

Adenocarcinoma Animals Antineoplastic Agents Apoptosis Cell Line, Tumor Disease Models, Animal Dopamine and cAMP-Regulated Phosphoprotein 32 Drug Resistance, Neoplasm ErbB Receptors Female Gefitinib Humans Mice Mice, Nude Phosphatidylinositol 3-Kinases Proto-Oncogene Proteins c-akt Quinazolines Receptor, ErbB-3 Signal Transduction Stomach Neoplasms

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