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Dig Dis Sci (2008) 53:101107 DOI 10.1007/s10620-007-9829-x
ORIGINAL PAPER
Reversal of Multidrug Resistance of Adriamycin-resistant Gastric Adenocarcinoma Cells Through the Up-regulation of DARPP-32
Liu Hong Yunping Zhao Jin Wang Ying Han Wei Guo Haifeng Jin Huihong Zhai Feihu Bai Xiaoyin Zhang Taidong Qiao Zhen Chen Daiming Fan
Received: 18 January 2007 / Accepted: 16 March 2007 / Published online: 11 May 2007 Springer Science+Business Media, LLC 2007
Abstract We have investigated the roles of dopamine and cAMP-regulated phosphoprotein (DARPP-32) in the multidrug resistance (MDR) of gastric cancer cells and the possible underlying mechanisms. The up-regulation of DARPP-32 was found to signicantly enhance the sensitivity of cells of human adriamycin (ADR)-resistant gastric adenocarcinoma cell line SGC7901/ADR to vincristine, ADR, 5-udrouracil and cisplatin. The results of an in vivo drug sensitivity assay conrmed that DARPP-32 may play a specic role in the MDR of gastric cancer. DARPP-32 signicantly down-regulated the expression of P-glyco-protein and zinc ribbon domain-containing 1 (ZNRD1), but did not alter the expression of MDR-associated protein or glutathione-S-transferase. The up-regulation of ZNRD1 signicantly inhibited the drug sensitivity of gastric cancer cells over-expressing DARPP-32, indicating that ZNRD1 may be important in the DARPP-32-mediated MDR of gastric cancer. DARPP-32 was also able to signicantly decrease the anti-apoptotic activity of SGC7901/ADR cells. Further study of the biological functions of DARPP-
32 may be helpful for understanding the mechanisms of MDR of gastric cancer cells and developing possible strategies to treat gastric cancer.
Keywords DARPP-32 Gastric neoplasm Multidrug resistance P-gp ZNRD1
Introduction
Multidrug resistance (MDR) is a major impediment to the effective chemotherapy of many human malignancies. A larger number of studies have revealed that diverse mechanisms are involved in the development of MDR, such as the extrusion of the drug by cell membrane pumps, increase of drug detoxication or DNA damage repair, redistribution of intracellular accumulation of drugs, modication of drug target molecules, suppression of drug-induced apoptosis, up-regulation of lipids, among other biochemical changes [17]. However, to date the precise mechanisms of MDR have not been completely elucidated, indicating that as yetunknown molecules are responsible for the development of MDR.
Dopamine and cAMP-regulated phosphoprotein (DARPP-32) is the only known bifunctional protein able to act as a PP1 (pyrazolo-pyrimidine) inhibitor or a protein kinase A (PKA) inhibitor [8]....