Differential regulation of c-Jun protein plays an instrumental role in chemoresistance of cancer cells.

TitleDifferential regulation of c-Jun protein plays an instrumental role in chemoresistance of cancer cells.
Publication TypeJournal Article
Year of Publication2013
AuthorsXia Y, Yang W, Bu W, Ji H, Zhao X, Zheng Y, Lin X, Li Y, Lu Z
JournalThe Journal of biological chemistry
Volume288
Issue27
Pagination19321-9
Date Published2013 Jul 5
Abstract

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 CDDP-resistant cancer cells promoted apoptosis upon CDDP treatment. In addition, mammary gland tumors induced by polyomavirus middle T antigen in JNK2(-/-) mice were more sensitive to CDDP compared with those in JNK2(+/+) mice. These findings highlight the instrumental role of c-Jun in the resistance of tumors to treatment with CDDP and indicate that c-Jun is a molecular target for improving cancer therapy.

DOI10.3969/j.issn.1672-7347.2013.06.001
Alternate JournalJ. Biol. Chem.