Cotylenin A inhibits cell proliferation and induces apoptosis and PAX6 mRNA transcripts in retinoblastoma cell lines.
OBJECTIVE
Retinoblastoma, a childhood cancer of the retina, is caused by inactivation of the tumor suppressor gene retinoblastoma (RB). Cotylenin A (CN-A), a novel fusicoccane-diterpene glycoside, accelerates the differentiation of several types of myeloid cell lines and is a candidate for a new type of anticancer therapeutic agent with this effect. However, whether CN-A has the same effect on retinoblastoma cells is unknown. We studied the response of two retinoblastoma cell lines, Y-79 and WERI-Rb-1, to CN-A.


METHODS
We studied the response of two retinoblastoma cell lines to CN-A with respect to cell growth, apoptosis, morphology, mRNA, protein expression analysis of specific genes (N-myc, cyclin-dependent kinase inhibitor 1A [P21], paired box gene 6 [PAX6], and rhodopsin [RHO]), and activity of three PAX6 promoters (P0, P1, and Palpha).


RESULTS
CN-A inhibited cell proliferation and induced apoptosis via caspase activity in the two retinoblastoma cell lines. In addition, CN-A induced mRNA expression of P21, PAX6, and RHO and protein expression of P21. In Y-79 cells, PAX6 P1 promoter was activated by CN-A. In WERI-Rb-1 cells, PAX6 P0, P1, and Palpha promoter were activated by CN-A. CN-A decreased mRNA and protein expression of N-myc in two retinoblastoma cell lines.


CONCLUSIONS
The responses of retinoblastoma cells to CN-A include inhibition of cell growth, induction of apoptosis, and the potential to change neuroblastoma characteristics of retinoblastoma cells.
Kashiwagi
Yoshiko
Y
Department of Ocular Cellular Engineering, Faculty of Medicine, Yamagata University, Yamagata City, Yamagata, Japan. kasiwagi@med.id.yamagata-u.ac.jp
Kato
Nobuo
N
Sassa
Takeshi
T
Nishitsuka
Koichi
K
Yamamoto
Teiko
T
Takamura
Hiroshi
H
Yamashita
Hidetoshi
H
D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004224:Diterpenes / Q000494:pharmacology*; D015536:Down-Regulation; D005091:Exons; D005136:Eye Proteins / Q000235:genetics*; D015870:Gene Expression / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics*; D012175:Retinoblastoma / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D012243:Rhodopsin / Q000235:genetics; D015854:Up-Regulation
D004224:Diterpenes; D005136:Eye Proteins; D056572:Histone Deacetylase Inhibitors; D018398:Homeodomain Proteins; D000071841:PAX6 Transcription Factor; C000605730:PAX6 protein, human; D051761:Paired Box Transcription Factors; D012333:RNA, Messenger; D012097:Repressor Proteins; C423222:cotylenin A; D012243:Rhodopsin; D020169:Caspases