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Targeting inhibitors of apoptosis proteins suppresses medulloblastoma cell proliferation via G2/M phase arrest and attenuated neddylation of p21

Medulloblastoma (MB) is the most common type of malignant childhood brain tumor. We previously showed that inhibitors of apoptosis proteins (IAP) small‐molecule inhibitors (LCL161 or LBW242) combined with chemotherapy have synergistic antiproliferative effects on MB cells. The synergistic antitumor...

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Autores principales: Chen, Shu‐Mei, Lin, Tzu‐Kang, Tseng, Yuan‐Yun, Tu, Chiao‐Hui, Lui, Tai‐Ngar, Huang, Shiang‐Fu, Hsieh, Ling‐Ling, Li, Ying‐Ying
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6089189/
https://www.ncbi.nlm.nih.gov/pubmed/29984917
http://dx.doi.org/10.1002/cam4.1658
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author Chen, Shu‐Mei
Lin, Tzu‐Kang
Tseng, Yuan‐Yun
Tu, Chiao‐Hui
Lui, Tai‐Ngar
Huang, Shiang‐Fu
Hsieh, Ling‐Ling
Li, Ying‐Ying
author_facet Chen, Shu‐Mei
Lin, Tzu‐Kang
Tseng, Yuan‐Yun
Tu, Chiao‐Hui
Lui, Tai‐Ngar
Huang, Shiang‐Fu
Hsieh, Ling‐Ling
Li, Ying‐Ying
author_sort Chen, Shu‐Mei
collection PubMed
description Medulloblastoma (MB) is the most common type of malignant childhood brain tumor. We previously showed that inhibitors of apoptosis proteins (IAP) small‐molecule inhibitors (LCL161 or LBW242) combined with chemotherapy have synergistic antiproliferative effects on MB cells. The synergistic antitumor effects of combination treatments happen through induction of autophagy and caspase‐3/7‐activated apoptosis. Here, we investigated the effects of IAP inhibitors or silencing IAP on cell cycle regulation. We discovered that treatment with IAP inhibitors or their combination with conventional chemotherapy (vincristine or cisplatin), as well as RNAi knockdown of cIAP1/2 or XIAP arrested MB cells in the G2/M phase through downregulation of cyclin B1‐CDK1 and cyclin A‐CDK1/2. Among these three IAPs, only silencing cIAP1 expression enhanced p21 dependent‐G2/M phase accumulation. IAP inhibitors reduced cIAP1 expression and increased p21 expression in time course experiments. Furthermore, cIAP1 can govern p21 proteasomal degradation via neddylation in lieu of ubiquitination. Inhibition of IAPs significantly abrogated cIAP1‐mediated p21 degradation. We also observed an inverse correlation between nuclear cIAP1 and nuclear p21 expressions in MB tumor tissues. These findings provide new mechanistic evidence of the influence of IAP inhibitors on MB cell proliferation through disruption of the cell cycle.
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spelling pubmed-60891892018-08-17 Targeting inhibitors of apoptosis proteins suppresses medulloblastoma cell proliferation via G2/M phase arrest and attenuated neddylation of p21 Chen, Shu‐Mei Lin, Tzu‐Kang Tseng, Yuan‐Yun Tu, Chiao‐Hui Lui, Tai‐Ngar Huang, Shiang‐Fu Hsieh, Ling‐Ling Li, Ying‐Ying Cancer Med Cancer Biology Medulloblastoma (MB) is the most common type of malignant childhood brain tumor. We previously showed that inhibitors of apoptosis proteins (IAP) small‐molecule inhibitors (LCL161 or LBW242) combined with chemotherapy have synergistic antiproliferative effects on MB cells. The synergistic antitumor effects of combination treatments happen through induction of autophagy and caspase‐3/7‐activated apoptosis. Here, we investigated the effects of IAP inhibitors or silencing IAP on cell cycle regulation. We discovered that treatment with IAP inhibitors or their combination with conventional chemotherapy (vincristine or cisplatin), as well as RNAi knockdown of cIAP1/2 or XIAP arrested MB cells in the G2/M phase through downregulation of cyclin B1‐CDK1 and cyclin A‐CDK1/2. Among these three IAPs, only silencing cIAP1 expression enhanced p21 dependent‐G2/M phase accumulation. IAP inhibitors reduced cIAP1 expression and increased p21 expression in time course experiments. Furthermore, cIAP1 can govern p21 proteasomal degradation via neddylation in lieu of ubiquitination. Inhibition of IAPs significantly abrogated cIAP1‐mediated p21 degradation. We also observed an inverse correlation between nuclear cIAP1 and nuclear p21 expressions in MB tumor tissues. These findings provide new mechanistic evidence of the influence of IAP inhibitors on MB cell proliferation through disruption of the cell cycle. John Wiley and Sons Inc. 2018-07-09 /pmc/articles/PMC6089189/ /pubmed/29984917 http://dx.doi.org/10.1002/cam4.1658 Text en © 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Cancer Biology
Chen, Shu‐Mei
Lin, Tzu‐Kang
Tseng, Yuan‐Yun
Tu, Chiao‐Hui
Lui, Tai‐Ngar
Huang, Shiang‐Fu
Hsieh, Ling‐Ling
Li, Ying‐Ying
Targeting inhibitors of apoptosis proteins suppresses medulloblastoma cell proliferation via G2/M phase arrest and attenuated neddylation of p21
title Targeting inhibitors of apoptosis proteins suppresses medulloblastoma cell proliferation via G2/M phase arrest and attenuated neddylation of p21
title_full Targeting inhibitors of apoptosis proteins suppresses medulloblastoma cell proliferation via G2/M phase arrest and attenuated neddylation of p21
title_fullStr Targeting inhibitors of apoptosis proteins suppresses medulloblastoma cell proliferation via G2/M phase arrest and attenuated neddylation of p21
title_full_unstemmed Targeting inhibitors of apoptosis proteins suppresses medulloblastoma cell proliferation via G2/M phase arrest and attenuated neddylation of p21
title_short Targeting inhibitors of apoptosis proteins suppresses medulloblastoma cell proliferation via G2/M phase arrest and attenuated neddylation of p21
title_sort targeting inhibitors of apoptosis proteins suppresses medulloblastoma cell proliferation via g2/m phase arrest and attenuated neddylation of p21
topic Cancer Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6089189/
https://www.ncbi.nlm.nih.gov/pubmed/29984917
http://dx.doi.org/10.1002/cam4.1658
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