Hyperphosphorylation of CDH1 in Glioblastoma Cancer Stem Cells Attenuates APC/CCDH1 Activity and Pharmacologic Inhibition of APC/CCDH1/CDC20 Compromises Viability.

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. IMPLICATIONS: Our findings demonstrate how the activity of the APC/CCDH1 tumor suppressor is reduced in CSCs and also validates small-molecule inhibition of the APC/C as a promising therapeutic target for the treatment of GBM.

• Authors: Kuntal De, Treg M Grubb, Abigail A Zalenski, Kayla E Pfaff, Debjani Pal, Shubhra Majumder, Matthew K Summers, Monica Venere
• Journal: Molecular cancer research : MCR (Mol Cancer Res) Vol. 17 Issue 7 Pg. 1519-1530 (07 2019) ISSN: 1557-3125 [Electronic] United States
• PMID: 31036696 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2019 American Association for Cancer Research.

Chemical References

• Antigens, CD
• CDH1 protein, human
• Cadherins
• Carbamates
• Cdc20 Proteins
• Cell Cycle Proteins
• Diamines
• F-Box Proteins
• FBXO5 protein, human
• Small Molecule Libraries
• apcin
• CDC20 protein, human
• Anaphase-Promoting Complex-Cyclosome

Topics

• Anaphase-Promoting Complex-Cyclosome (antagonists & inhibitors, genetics)
• Antigens, CD (genetics)
• Cadherins (antagonists & inhibitors, genetics)
• Carbamates (pharmacology)
• Cdc20 Proteins (genetics)
• Cell Cycle Proteins (genetics)
• Cell Survival (drug effects, genetics)
• Diamines (pharmacology)
• F-Box Proteins (genetics)
• Glioblastoma (drug therapy, genetics, pathology)
• Humans
• Mitosis (drug effects, genetics)
• Neoplastic Stem Cells (drug effects)
• Phosphorylation (drug effects)
• Small Molecule Libraries (pharmacology)