Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
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Target Concepts:
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Query: UMLS:C0033036 (
APC
)
10,214
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Glioblastoma
harbors a dynamic subpopulation of glioblastoma stem-like cells (GSCs) that can propagate tumors in vivo and is resistant to standard chemoradiation. Identification of the cell-intrinsic mechanisms governing this clinically important cell state may lead to the discovery of therapeutic strategies for this challenging malignancy. Here, we demonstrate that the mitotic E3 ubiquitin ligase CDC20-anaphase-promoting complex (CDC20-APC) drives invasiveness and self-renewal in patient tumor-derived GSCs. Moreover, CDC20 knockdown inhibited and CDC20 overexpression increased the ability of human GSCs to generate brain tumors in an orthotopic xenograft model in vivo. CDC20-
APC
control of GSC invasion and self-renewal operates through pluripotency-related transcription factor SOX2. Our results identify a CDC20-
APC
/SOX2 signaling axis that controls key biological properties of GSCs, with implications for CDC20-
APC
-targeted strategies in the treatment of glioblastoma.
...
PMID:A CDC20-APC/SOX2 Signaling Axis Regulates Human Glioblastoma Stem-like Cells. 2607 73
Glioblastoma
stem-like cells (GSCs) play a critical role in glioblastoma progression and recurrence. We discuss recent results on the role of the mitotic ubiquitin ligase cell division cycle 20-anaphase-promoting complex (CDC20-APC) in the governance of cardinal GSC functions through a mechanism involving the transcription factor sex-determining region Y-box 2 (SOX2). These findings expand the non-mitotic roles of CDC20-
APC
with implications for stem cell biology.
...
PMID:The CDC20-APC/SOX2 signaling axis: An achilles' heel for glioblastoma. 2731 81
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
CDH1
activity in the G
1
-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
CDH1
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
.
...
PMID:Hyperphosphorylation of CDH1 in Glioblastoma Cancer Stem Cells Attenuates APC/C
CDH1
Activity and Pharmacologic Inhibition of APC/C
CDH1/CDC20
Compromises Viability. 3103 96
