title: Differential regulation of c-Jun protein plays an instrumental role in chemoresistance of cancer cells.
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.
authors.affiliation: Brain Tumor Center and Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
authors.forename: Yan
authors.initials: Y
authors.lastname: Xia
authors.forename: Weiwei
authors.initials: W
authors.lastname: Yang
authors.forename: Wen
authors.initials: W
authors.lastname: Bu
authors.forename: Haitao
authors.initials: H
authors.lastname: Ji
authors.forename: Xueqiang
authors.initials: X
authors.lastname: Zhao
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Zheng
authors.forename: Xin
authors.initials: X
authors.lastname: Lin
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Lu
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D053453:Caspase 9 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D005260:Female; D006801:Humans; D048728:MAP Kinase Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D048056:Mitogen-Activated Protein Kinase 9 / Q000235:genetics / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects / Q000235:genetics
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D016755:Proto-Oncogene Proteins c-jun; D048056:Mitogen-Activated Protein Kinase 9; D048728:MAP Kinase Kinase Kinase 1; C506434:Casp9 protein, mouse; D053453:Caspase 9; D002945:Cisplatin
keywords: Apoptosis; Caspase; Jun Transcription Factor; Ubiquitin; c-Jun; c-Jun N-terminal Kinase (JNK)