Targeting Aurora A Kinase (AAK) in Platinum-Resistant High Grade Serous Ovarian Cancer
Aurora A kinase (AAK) involved in G2-M transition is functionally involved in centrosome maturation and maintaining an active spindle assembly checkpoint. We tested the hypothesis that in platinum-taxane resistant high grade serous ovarian cancer (HGSOC) inhibition of AAK involved in G2-M transition...
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Frontiers Media S.A.
2020-08-01
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doaj-cdaebad91e714c29be25e0047bbfb87e2020-11-25T03:23:36ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2020-08-011010.3389/fonc.2020.01354545942Targeting Aurora A Kinase (AAK) in Platinum-Resistant High Grade Serous Ovarian CancerRam N. GanapathiEric J. NorrisAshley P. SutkerKaitlin E. KlotzMahrukh K. GanapathiAurora A kinase (AAK) involved in G2-M transition is functionally involved in centrosome maturation and maintaining an active spindle assembly checkpoint. We tested the hypothesis that in platinum-taxane resistant high grade serous ovarian cancer (HGSOC) inhibition of AAK involved in G2-M transition would enhance the anti-tumor activity of cisplatin (CP) or paclitaxel (PT). Using HGSOC cell lines from platinum-taxane refractory patients that do not harbor BRCA1/2 mutations, we tested the anti-tumor activity of CP, or PT alone or in combination with the AAK inhibitor alisertib (AL). Treatment with CP for 3 h or PT for 6 h followed sequentially by AL for 48 h led to a significant decrease in cell survival (p < 0.001) compared to treatment with either drug alone in HGSOC cells but not in immortalized normal human ovarian surface epithelium or normal human fallopian tube secretory epithelium cells. The treatment with CP or PT followed by AL also led to a significant increase in reactive oxygen species (p < 0.05), apoptosis (p < 0.001) and accumulation of cells in G2/M that was accompanied by a modest increase in expression of AAK. Downregulation of AAK, but not aurora B kinase, with targeted siRNAs also significantly enhanced apoptosis by CP or PT, suggesting that AL specifically targeted AAK. In summary, in HGSOC without BRCA1/2 mutations, CP, or PT resistance can potentially be circumvented by sequential treatment with AL that inhibits AAK involved in G2-M transition.https://www.frontiersin.org/article/10.3389/fonc.2020.01354/fullaurora A kinasehigh grade serous ovarian cancerplatinum-resistancealisertibBRCA |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ram N. Ganapathi Eric J. Norris Ashley P. Sutker Kaitlin E. Klotz Mahrukh K. Ganapathi |
spellingShingle |
Ram N. Ganapathi Eric J. Norris Ashley P. Sutker Kaitlin E. Klotz Mahrukh K. Ganapathi Targeting Aurora A Kinase (AAK) in Platinum-Resistant High Grade Serous Ovarian Cancer Frontiers in Oncology aurora A kinase high grade serous ovarian cancer platinum-resistance alisertib BRCA |
author_facet |
Ram N. Ganapathi Eric J. Norris Ashley P. Sutker Kaitlin E. Klotz Mahrukh K. Ganapathi |
author_sort |
Ram N. Ganapathi |
title |
Targeting Aurora A Kinase (AAK) in Platinum-Resistant High Grade Serous Ovarian Cancer |
title_short |
Targeting Aurora A Kinase (AAK) in Platinum-Resistant High Grade Serous Ovarian Cancer |
title_full |
Targeting Aurora A Kinase (AAK) in Platinum-Resistant High Grade Serous Ovarian Cancer |
title_fullStr |
Targeting Aurora A Kinase (AAK) in Platinum-Resistant High Grade Serous Ovarian Cancer |
title_full_unstemmed |
Targeting Aurora A Kinase (AAK) in Platinum-Resistant High Grade Serous Ovarian Cancer |
title_sort |
targeting aurora a kinase (aak) in platinum-resistant high grade serous ovarian cancer |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Oncology |
issn |
2234-943X |
publishDate |
2020-08-01 |
description |
Aurora A kinase (AAK) involved in G2-M transition is functionally involved in centrosome maturation and maintaining an active spindle assembly checkpoint. We tested the hypothesis that in platinum-taxane resistant high grade serous ovarian cancer (HGSOC) inhibition of AAK involved in G2-M transition would enhance the anti-tumor activity of cisplatin (CP) or paclitaxel (PT). Using HGSOC cell lines from platinum-taxane refractory patients that do not harbor BRCA1/2 mutations, we tested the anti-tumor activity of CP, or PT alone or in combination with the AAK inhibitor alisertib (AL). Treatment with CP for 3 h or PT for 6 h followed sequentially by AL for 48 h led to a significant decrease in cell survival (p < 0.001) compared to treatment with either drug alone in HGSOC cells but not in immortalized normal human ovarian surface epithelium or normal human fallopian tube secretory epithelium cells. The treatment with CP or PT followed by AL also led to a significant increase in reactive oxygen species (p < 0.05), apoptosis (p < 0.001) and accumulation of cells in G2/M that was accompanied by a modest increase in expression of AAK. Downregulation of AAK, but not aurora B kinase, with targeted siRNAs also significantly enhanced apoptosis by CP or PT, suggesting that AL specifically targeted AAK. In summary, in HGSOC without BRCA1/2 mutations, CP, or PT resistance can potentially be circumvented by sequential treatment with AL that inhibits AAK involved in G2-M transition. |
topic |
aurora A kinase high grade serous ovarian cancer platinum-resistance alisertib BRCA |
url |
https://www.frontiersin.org/article/10.3389/fonc.2020.01354/full |
work_keys_str_mv |
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