Abstract
Glioblastoma (GBM) is the most common and lethal primary brain tumor and remains incurable. This is in part due to the cellular heterogeneity within these tumors, which includes a subpopulation of treatment-resistant cells called cancer stem-like cells (CSC). We previously identified that the anaphase-promoting complex/cylosome (APC/C), a key cell-cycle regulator and tumor suppressor, had attenuated ligase activity in CSCs. Here, we assessed the mechanism of reduced activity, as well as the efficacy of pharmacologically targeting the APC/C in CSCs. We identified hyperphosphorylation of CDH1, but not pseudosubstrate inhibition by early mitotic inhibitor 1 (EMI1), as a major mechanism driving attenuated APC/CCDH1 activity in the G1-phase of the cell cycle in CSCs. Small-molecule inhibition of the APC/C reduced viability of both CSCs and nonstem tumor cells (NSTCs), with the combination of proTAME and apcin having the biggest impact. Combinatorial drug treatment also led to the greatest mitotic arrest and chromosomal abnormalities.
| Original language | English |
|---|---|
| Pages (from-to) | 1519-1530 |
| Number of pages | 12 |
| Journal | Molecular Cancer Research |
| Volume | 17 |
| Issue number | 7 |
| DOIs | |
| State | Published - Jul 1 2019 |
| Externally published | Yes |
Funding
The authors thank Dr. Liwen Zhang of the Proteomics Shared Resource at The Ohio State Comprehensive Cancer Center and Dr. Belinda Willard of the Lerner Research Institute Mass Spectrometry Laboratory for Protein Sequencing at the Cleveland Clinic Foundation for sample processing and analysis. We also thank members of the Venere laboratory for insightful discussion and constructive comments on the article. This work was supported by a Research Scholar Grant, RSG-18-066-01-TBG, from the American Cancer Society, an Internal Research Program Grant from The Ohio State University Comprehensive Cancer Center, and The Ohio State University Comprehensive Cancer Center/Department of Radiation Oncology start-up funds (to M. Venere); the Heritage College of Osteopathic Medicine Medical Student Research Seed Funding (to K.E. Pfaff); and R01GM112895 and R01GM108743 (to M.K. Summers). The Fusion Lumos instrument from the Lerner Research Institute Mass Spectrometry Laboratory for Protein Sequencing at the Cleveland Clinic Foundation was purchased via an NIH shared instrument grant, 1S10OD023436–01. Research reported in the publication was supported by The Ohio State University Comprehensive Cancer Center and the NIH under grant number P30 CA016058.
| Funders | Funder number |
|---|---|
| Heritage College of Osteopathic Medicine Medical Student Research Seed Funding | R01GM112895, R01GM108743 |
| Lerner Research Institute Mass Spectrometry Laboratory | |
| Ohio State University Comprehensive Cancer Center | |
| Ohio State University Comprehensive Cancer Center/Department | |
| National Institutes of Health | 1S10OD023436–01, P30 CA016058 |
| American Cancer Society |
