Identification of PLK1 as a New Therapeutic Target in Mucinous Ovarian Carcinoma
Mucinous epithelial ovarian cancer (mEOC) is a rare subset of epithelial ovarian cancer. When diagnosed at a late stage, its prognosis is very poor, as it is quite chemo-resistant. To find new therapeutic options for mEOC, we performed high-throughput screening using a siRNA library directed against...
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doaj-151c15c44df14cf39ebdda816ca5ecd12020-11-25T02:52:23ZengMDPI AGCancers2072-66942020-03-0112367210.3390/cancers12030672cancers12030672Identification of PLK1 as a New Therapeutic Target in Mucinous Ovarian CarcinomaRoberta Affatato0Laura Carrassa1Rosaria Chilà2Monica Lupi3Valentina Restelli4Giovanna Damia5Laboratory of Molecular Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri-IRCCS, Via Mario Negri 2, 20156 Milan, ItalyLaboratory of Molecular Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri-IRCCS, Via Mario Negri 2, 20156 Milan, ItalyLaboratory of Molecular Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri-IRCCS, Via Mario Negri 2, 20156 Milan, ItalyLaboratory of Molecular Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri-IRCCS, Via Mario Negri 2, 20156 Milan, ItalyLaboratory of Molecular Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri-IRCCS, Via Mario Negri 2, 20156 Milan, ItalyLaboratory of Molecular Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri-IRCCS, Via Mario Negri 2, 20156 Milan, ItalyMucinous epithelial ovarian cancer (mEOC) is a rare subset of epithelial ovarian cancer. When diagnosed at a late stage, its prognosis is very poor, as it is quite chemo-resistant. To find new therapeutic options for mEOC, we performed high-throughput screening using a siRNA library directed against human protein kinases in a mEOC cell line, and polo-like kinase1 (PLK1) was identified as the kinase whose downregulation interfered with cell proliferation. Both PLK1 siRNA and two specific PLK1 inhibitors (onvansertib and volasertib) were able to inhibit cell growth, induce apoptosis and block cells in the G2/M phase of the cell cycle. We evaluated, in vitro, the combinations of PLK1 inhibitors and different chemotherapeutic drugs currently used in the treatment of mEOC, and we observed a synergistic effect of PLK1 inhibitors and antimitotic drugs. When translated into an in vivo xenograft model, the combination of onvansertib and paclitaxel resulted in stronger tumor regressions and in a longer mice survival than the single treatments. These effects were associated with a higher induction of mitotic block and induction of apoptosis, similarly to what was observed in vitro. These data suggest that the combination onvansertib/paclitaxel could represent a new active therapeutic option in mEOC.https://www.mdpi.com/2072-6694/12/3/672screeningplk1mucinous ovarian carcinoma |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Roberta Affatato Laura Carrassa Rosaria Chilà Monica Lupi Valentina Restelli Giovanna Damia |
spellingShingle |
Roberta Affatato Laura Carrassa Rosaria Chilà Monica Lupi Valentina Restelli Giovanna Damia Identification of PLK1 as a New Therapeutic Target in Mucinous Ovarian Carcinoma Cancers screening plk1 mucinous ovarian carcinoma |
author_facet |
Roberta Affatato Laura Carrassa Rosaria Chilà Monica Lupi Valentina Restelli Giovanna Damia |
author_sort |
Roberta Affatato |
title |
Identification of PLK1 as a New Therapeutic Target in Mucinous Ovarian Carcinoma |
title_short |
Identification of PLK1 as a New Therapeutic Target in Mucinous Ovarian Carcinoma |
title_full |
Identification of PLK1 as a New Therapeutic Target in Mucinous Ovarian Carcinoma |
title_fullStr |
Identification of PLK1 as a New Therapeutic Target in Mucinous Ovarian Carcinoma |
title_full_unstemmed |
Identification of PLK1 as a New Therapeutic Target in Mucinous Ovarian Carcinoma |
title_sort |
identification of plk1 as a new therapeutic target in mucinous ovarian carcinoma |
publisher |
MDPI AG |
series |
Cancers |
issn |
2072-6694 |
publishDate |
2020-03-01 |
description |
Mucinous epithelial ovarian cancer (mEOC) is a rare subset of epithelial ovarian cancer. When diagnosed at a late stage, its prognosis is very poor, as it is quite chemo-resistant. To find new therapeutic options for mEOC, we performed high-throughput screening using a siRNA library directed against human protein kinases in a mEOC cell line, and polo-like kinase1 (PLK1) was identified as the kinase whose downregulation interfered with cell proliferation. Both PLK1 siRNA and two specific PLK1 inhibitors (onvansertib and volasertib) were able to inhibit cell growth, induce apoptosis and block cells in the G2/M phase of the cell cycle. We evaluated, in vitro, the combinations of PLK1 inhibitors and different chemotherapeutic drugs currently used in the treatment of mEOC, and we observed a synergistic effect of PLK1 inhibitors and antimitotic drugs. When translated into an in vivo xenograft model, the combination of onvansertib and paclitaxel resulted in stronger tumor regressions and in a longer mice survival than the single treatments. These effects were associated with a higher induction of mitotic block and induction of apoptosis, similarly to what was observed in vitro. These data suggest that the combination onvansertib/paclitaxel could represent a new active therapeutic option in mEOC. |
topic |
screening plk1 mucinous ovarian carcinoma |
url |
https://www.mdpi.com/2072-6694/12/3/672 |
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