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Abstract
In addition to their original function as cell cycle regulators, retinoblastoma (Rb) family members were recently reported to modulate the sensitivity of cancer cells to chemotherapeutic agents. The purpose of this study is to investigate the possible role of pRb2/p130 in the sensitivity of ovarian cancer to camptothecin, doxorubicin, and taxol. pRb2/p130 was overexpressed in the CAOV-3 ovarian cancer cell line, and the effect of pRb2/p130 overexpression on sensitivity to apoptosis trigged by IC(50) doses of different drugs was evaluated by various methods, including 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, flow cytometry, and Western blot analyses. The results reported in this study support the conclusion that overexpression of pRb2/p130 in the CAOV-3 ovarian cancer cell line lacking wild-type p53 is able to inhibit apoptosis triggered by camptothecin and doxorubicin through the c-Jun NH(2)-terminal kinase signaling transduction pathway. Conversely, taxol-induced cell death is not influenced by the pRb2/p130 protein level. A careful analysis of pRb2/p130 expression in tumor specimens could help to identify the best clinical protocol to be used for each patient, improving efficacy and tolerance and therefore offering additional progress in the treatment of advanced ovarian cancer.
Highlights
To date, ovarian cancer remains a disease with a poor prognosis, even though improvements in earlier diagnosis and novel therapies over the past 20 years have led to significant survival rates
Consistent with these data, we demonstrate that both CPT and DOX induce apoptosis in CAOV-3 cells through control of the c-Jun expression level and c-Jun phosphorylation status
The CAOV-3 ovarian carcinoma cell line was obtained from American Type Culture Collection (Manassas, VA) and grown at 37°C in a 5% CO2/95% air atmosphere in Dulbecco’s modified Eagle’s medium (DMEM; Mediatech Inc., Herndon, VA) supplemented with 10% fetal bovine serum (FBS; Mediatech Inc.)
Summary
Ovarian cancer remains a disease with a poor prognosis, even though improvements in earlier diagnosis and novel therapies over the past 20 years have led to significant survival rates. Numerous cellular stresses including DNA-damaging agents such as topoisomerase I and II inhibitors initiate the apoptotic pathway through the activation of c-Jun NH2-terminal kinase (JNK) with a consequent increase in the phosphorylation of c-Jun and induction of activator protein-1– mediated transcription (24 –26) Consistent with these data, we demonstrate that both CPT and DOX induce apoptosis in CAOV-3 cells through control of the c-Jun expression level and c-Jun phosphorylation status. The different apoptotic signaling pathways for CPT, DOX, and TX could contribute to a greater effectiveness in chemotherapy when these agents are used in combination rather than alone These findings highlight an antiapoptotic role of pRb2/p130 in CPT- and DOX-mediated cell death and suggest the importance of analyzing pRb2/p130 expression in tumor specimens because it is likely to influence the outcome of chemotherapy
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