Journal
GASTROENTEROLOGY
Volume 141, Issue 5, Pages 1738-U297Publisher
W B SAUNDERS CO-ELSEVIER INC
DOI: 10.1053/j.gastro.2011.06.070
Keywords
Stomach Cancer; Treatment; PI3K; AKT; Drug Resistance; PPP1R1B; Dopamine Signaling
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Funding
- National Institute of Health [R01CA93999]
- Vanderbilt SPORE in Gastrointestinal Cancer [P50 CA95103]
- Vanderbilt Ingram Cancer Center [P30 CA68485]
- Vanderbilt Digestive Disease Research Center [DK058404]
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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 IC50 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.
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