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

Abstract

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.

• Authors: Shu-Mei Chen, Tzu-Kang Lin, Yuan-Yun Tseng, Chiao-Hui Tu, Tai-Ngar Lui, Shiang-Fu Huang, Ling-Ling Hsieh, Ying-Ying Li
• Journal: Cancer medicine (Cancer Med) Vol. 7 Issue 8 Pg. 3988-4003 (08 2018) ISSN: 2045-7634 [Electronic] United States
• PMID: 29984917 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Chemical References

• Antineoplastic Agents
• Apoptosis Regulatory Proteins
• Biomarkers
• Cyclin-Dependent Kinase Inhibitor p21
• Cyclin-Dependent Kinases

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects, genetics)
• Apoptosis Regulatory Proteins (antagonists & inhibitors, genetics, metabolism)
• Biomarkers
• Cell Line, Tumor
• Cyclin-Dependent Kinase Inhibitor p21 (genetics, metabolism)
• Cyclin-Dependent Kinases (metabolism)
• Dose-Response Relationship, Drug
• G2 Phase Cell Cycle Checkpoints (drug effects, genetics)
• Gene Expression Regulation, Neoplastic
• Gene Knockdown Techniques
• Humans
• Medulloblastoma (genetics, metabolism)
• Protein Processing, Post-Translational