Estrogen-dependent cell signaling and apoptosis in BRCA1-blocked BG1 ovarian cancer cells in response to plumbagin and other chemotherapeutic agents.
BACKGROUND
Cellular response to chemotherapeutic drugs in the absence of BRCA1 either completely or partially had drawn less attention. The present study evaluated whether there is a differential inhibition of cell growth by selected compounds with respect to BRCA1 status in estrogen receptor (ER)-positive ovarian cancer cells.


METHODS
The BG1 ovarian cancer cells used in the experiments were antisensely blocked with BRCA1 gene. Growth inhibition and apoptotic induction were analyzed to evaluate the cytotoxic effects. Small interfering RNA (SiRNA) transfection, western blot analysis, RT-PCR analysis and molecular modeling were carried out to analyze the estrogen-dependent action of plumbagin.


RESULTS
Although we found that all the compounds studied induce apoptosis, the induction was in the order of plumbagin > doxorubicin > tamoxifen > cisplatin. Plumbagin can bind to the active site of ER-alpha. Plumbagin, however, induced ER-alpha 46 kDa truncated isoform, which was found abundantly preempted in the cytoplasm compared with a 66-kDa full-length isoform. The truncated isoform is known to inhibit classical ER-alpha signaling pathways. SiRNA-transfected cells for ER-alpha exhibited lower cytotoxicity upon plumbagin treatment than the control-transfected cells.


CONCLUSIONS
Taken together, this study indicates that plumbagin has chemotherapeutic potential in BRCA1-mutated/defective ER-positive cancers.
Thasni
K A
KA
Laboratory of Molecular Therapeutics, Rajiv Gandhi Centre for Biotechnology, Thycaud PO, Thiruvananthapuram, Kerala.
Rakesh
S
S
Rojini
G
G
Ratheeshkumar
T
T
Srinivas
G
G
Priya
S
S
D000199:Actins / Q000378:metabolism; D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D000970:Antineoplastic Agents / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000378:metabolism; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D019398:Genes, BRCA1; D006801:Humans; D007928:Lethal Dose 50; D009285:Naphthoquinones / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D013629:Tamoxifen / Q000494:pharmacology; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
D000199:Actins; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D014408:Biomarkers, Tumor; D047628:Estrogen Receptor alpha; D009285:Naphthoquinones; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D013629:Tamoxifen; D004317:Doxorubicin; C102449:BARD1 protein, human; D044767:Ubiquitin-Protein Ligases; D002945:Cisplatin; C014758:plumbagin