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

• Published in: Molecular cancer research 2019-07, Vol.17 (7), p.1519
• Main Authors: De, Kuntal, Grubb, Treg M, Zalenski, Abigail A, Pfaff, Kayla E, Pal, Debjani, Majumder, Shubhra, Summers, Matthew K, Venere, Monica
• Format: Article
• Language: English
• Subjects: Anaphase-Promoting Complex-Cyclosome - antagonists & inhibitors; Anaphase-Promoting Complex-Cyclosome - genetics; Antigens, CD - genetics; Cadherins - antagonists & inhibitors; Cadherins - genetics; Carbamates - pharmacology; Cdc20 Proteins - genetics; Cell Cycle Proteins - genetics; Cell Survival - drug effects; Cell Survival - genetics; Diamines - pharmacology; F-Box Proteins - genetics; Glioblastoma - drug therapy; Glioblastoma - genetics; Glioblastoma - pathology; Humans; Mitosis - drug effects; Mitosis - genetics; Neoplastic Stem Cells - drug effects; Phosphorylation - drug effects; Small Molecule Libraries - pharmacology
• ISSN: 1557-3125
• DOI: 10.1158/1541-7786.MCR-18-1361

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/C activity in the G -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/C 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.