TY - JOUR
T1 - Differential regulation of c-Jun protein plays an instrumental role in chemoresistance of cancer cells
AU - Xia, Yan
AU - Yang, Weiwei
AU - Bu, Wen
AU - Ji, Haitao
AU - Zhao, Xueqiang
AU - Zheng, Yanhua
AU - Lin, Xin
AU - Li, Yi
AU - Lu, Zhimin
PY - 2013/7/5
Y1 - 2013/7/5
N2 - The chemotherapeutic drug cisplatin (cis-diamminedichloroplatinum( II) (CDDP)) is widely used in the treatment of human cancers. However, the mechanism underlying intrinsic tumor resistance to CDDP remains elusive. Here, we demonstrate that treatment with CDDP resulted in down-regulation of c-Jun expression via caspase-9-dependent cleavage of c-Jun at Asp-65 and MEKK1-mediated ubiquitylation and degradation of c-Jun in CDDP-sensitive cancer cells. In contrast, activation of JNK2 (but not JNK1) phosphorylated and up-regulated the expression of c-Jun in CDDP-resistant cells. Activated c-Jun bound to the promoter regions of the MDR1 gene and promoted the expression of MDR1. Expression of a cleavage-resistant c-Jun mutant (D65A) suppressed CDDP-induced apoptosis of CDDP-sensitive cells, whereas depletion of JNK2, c-Jun, or MDR1 in CDDPresistant cancer cells promoted apoptosis upon CDDP treatment. In addition, mammary gland tumors induced by polyomavirus middle T antigen in JNK2-/- mice were more sensitive toCDDPcompared with those in JNK2-/- mice. These findings highlight the instrumental role of c-Jun in the resistance of tumors to treatment withCDDPand indicate that c-Jun is a molecular target for improving cancer therapy.
AB - The chemotherapeutic drug cisplatin (cis-diamminedichloroplatinum( II) (CDDP)) is widely used in the treatment of human cancers. However, the mechanism underlying intrinsic tumor resistance to CDDP remains elusive. Here, we demonstrate that treatment with CDDP resulted in down-regulation of c-Jun expression via caspase-9-dependent cleavage of c-Jun at Asp-65 and MEKK1-mediated ubiquitylation and degradation of c-Jun in CDDP-sensitive cancer cells. In contrast, activation of JNK2 (but not JNK1) phosphorylated and up-regulated the expression of c-Jun in CDDP-resistant cells. Activated c-Jun bound to the promoter regions of the MDR1 gene and promoted the expression of MDR1. Expression of a cleavage-resistant c-Jun mutant (D65A) suppressed CDDP-induced apoptosis of CDDP-sensitive cells, whereas depletion of JNK2, c-Jun, or MDR1 in CDDPresistant cancer cells promoted apoptosis upon CDDP treatment. In addition, mammary gland tumors induced by polyomavirus middle T antigen in JNK2-/- mice were more sensitive toCDDPcompared with those in JNK2-/- mice. These findings highlight the instrumental role of c-Jun in the resistance of tumors to treatment withCDDPand indicate that c-Jun is a molecular target for improving cancer therapy.
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U2 - 10.1074/jbc.M113.475442
DO - 10.1074/jbc.M113.475442
M3 - Article
C2 - 23678002
AN - SCOPUS:84880048265
SN - 0021-9258
VL - 288
SP - 19321
EP - 19329
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 27
ER -