RRC ID 18994
Author Suzuki A, Horiuchi A, Ashida T, Miyamoto T, Kashima H, Nikaido T, Konishi I, Shiozawa T.
Title Cyclin A2 confers cisplatin resistance to endometrial carcinoma cells via up-regulation of an Akt-binding protein, periplakin.
Journal J. Cell. Mol. Med.
Abstract Although overexpression of cyclin A2 is reportedly an indicator of a poor prognosis of various malignancies including endometrial carcinoma, its molecular mechanism remains undetermined. To address this issue, we examined the effect of cyclin A2 on the development of resistance to chemotherapeutic drugs. The expression of cyclin A2 protein was increased in advanced-stage and chemotherapy-refractory stage endometrial carcinomas compared with that in early-stage tumours. The expression levels of cyclin A2 in endometrial carcinoma cell lines correlated positively with the IC(50) for cisplatin. Endometrial carcinoma HHUA cells that overexpressed cyclin A2 showed increased resistance to cisplatin in vitro and in vivo, via the activation of a survival pathway, the inositol-3 phosphate kinase (PI3K) cascade. The use of a cDNA microarray identified an Akt-binding protein, periplakin, as a novel target of cyclin A2. The cyclin A2-induced up-regulation of periplakin was mediated via direct binding of Sp1 to the promoter that was activated by cyclin A2 along with chromatin remodelling involving CBP/p300, and the siRNA-mediated silencing of periplakin suppressed the PI3K pathway. These results indicate cyclin A2 to be involved in the acquisition of aggressive behaviour of tumour cells through the activation of PI3K by cyclin A2-induced periplakin, and to be a promising therapeutic target.
Volume 14(9)
Pages 2305-17
Published 2010-9
DOI 10.1111/j.1582-4934.2009.00839.x
PMID 19583808
PMC PMC3822571
MeSH Animals Apoptosis / drug effects Binding Sites Cell Line, Tumor Cell Proliferation / drug effects Cisplatin / pharmacology* Cyclin A2 / metabolism* Drug Resistance, Neoplasm / drug effects* Endometrial Neoplasms / enzymology Endometrial Neoplasms / genetics Endometrial Neoplasms / pathology* Enzyme Activation / drug effects Female Gene Expression Regulation, Neoplastic / drug effects Humans Mice Mice, Inbred BALB C Oligonucleotide Array Sequence Analysis Phosphatidylinositol 3-Kinases / metabolism Plakins / genetics Plakins / metabolism* Promoter Regions, Genetic / genetics Protein Binding / drug effects Proto-Oncogene Proteins c-akt / metabolism* Reproducibility of Results Signal Transduction / drug effects Sp1 Transcription Factor / metabolism Up-Regulation / drug effects*
IF 4.658
Times Cited 9
Human and Animal Cells HHUA (RCB0658)