Cyclin A2 confers cisplatin resistance to endometrial carcinoma cells via up-regulation of an Akt-binding protein, periplakin.
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.
Suzuki
Akihisa
A
Department of Obstetrics and Gynecology, Shinshu University School of Medicine, Matsumoto, Japan.
Horiuchi
Akiko
A
Ashida
Takashi
T
Miyamoto
Tsutomu
T
Kashima
Hiroyasu
H
Nikaido
Toshio
T
Konishi
Ikuo
I
Shiozawa
Tanri
T
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D056751:Cyclin A2 / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D016889:Endometrial Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D020411:Oligonucleotide Array Sequence Analysis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051179:Plakins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000187:drug effects; D016329:Sp1 Transcription Factor / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects*
D056751:Cyclin A2; C491674:PPL protein, human; D051179:Plakins; D016329:Sp1 Transcription Factor; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D002945:Cisplatin