Abstract
Prostate apoptosis response-4 (PAR-4) is considered as a tumour suppressor due to its ability to selectively induce cell apoptosis in most cancer cells. However little is known about the role of PAR-4 in ovarian cancer. In this study, we investigated for the first time the role of PAR-4 in ovarian carcinogenesis. We showed that PAR-4 mRNA level is not significantly different between healthy and cancer ovarian cells. Immunohistochemistry on ovarian tissue showed that ovarian cancer cells are positive for PAR-4 nuclear and cytoplasmic staining whereas ovarian healthy cells are negative for PAR-4 nuclear staining. We then studied the role of PAR-4 in cell apoptosis. We determined that PAR-4 induces cell apoptosis in response to stimuli, in vitro, but is also involved in the relocation of GRP78 from endoplasmic reticulum to the cell surface of ovarian cancer cell line (SKOV-3 cells). In ovo, PAR-4 decreases ovarian tumour development and increases the response to taxol treatment. These observations suggest that PAR-4 is a very interesting therapeutic target against ovarian carcinogenesis.
Highlights
Ovarian cancer is the leading cause of death for gynaecological cancers and the seventh highest cause of cancer death in women [1]
Prostate apoptosis response-4 (PAR-4) can be translocated to the nucleus where it inhibits the NF-ĸBmediated transcription of survival genes or the action of TOPO1 [4]
PAR-4 mediated-apoptosis could www.impactjournals.com/oncotarget be impeded in cancer cells either by a downregulation of PAR-4 expression and/or by decreased activity of PAR-4 due to its non-phosphorylation or its sequestration in cytoplasm preventing its entry into the nucleus [4]
Summary
Ovarian cancer is the leading cause of death for gynaecological cancers and the seventh highest cause of cancer death in women [1]. The International Federation of Gynaecology and Obstetrics (FIGO) classifies ovarian cancer in 4 main stages which progressively increase in severity [2]. This disease is generally detected late at stages 3 and 4 due to poor specificity of early detection methods. The standard treatment combines surgical cytoreduction with a combination of chemotherapies. Despite this aggressive approach, the 5 year survival rate is around 30% for all stages involved [3]. In order to develop new therapeutic approaches, it is important to better understand the pathological mechanisms involved in ovarian tumorigenesis
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