American Association for Cancer Research
Browse
15417786mcr181361-sup-214342_3_supp_5461382_pq0j77.pdf (586.45 kB)

Supplementary Figure S2 from Hyperphosphorylation of CDH1 in Glioblastoma Cancer Stem Cells Attenuates APC/CCDH1 Activity and Pharmacologic Inhibition of APC/CCDH1/CDC20 Compromises Viability

Download (586.45 kB)
journal contribution
posted on 2023-04-03, 16:49 authored by Kuntal De, Treg M. Grubb, Abigail A. Zalenski, Kayla E. Pfaff, Debjani Pal, Shubhra Majumder, Matthew K. Summers, Monica Venere

Nocodazole synchronization for GBM NSTCs

Funding

American Cancer Society

Heritage College of Osteopathic Medicine Medical Student Research Seed Funding

Ohio State University Comprehensive Cancer Center

NIH

History

ARTICLE 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. 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.