Proteasome Inhibition Suppresses KIT-Independent Gastrointestinal Stromal Tumors Via Targeting Hippo/YAP/Cyclin D1 Signaling
Purpose: Gastrointestinal stromal tumors (GISTs) are the most common malignant tumor of mesenchymal origin of the digestive tract. A yet more challenging resistance mechanism involves transition from oncogenic KIT to a new imatinib-insensitive oncogenic driver, heralded by loss of KIT expression. Ou...
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Published in | Frontiers in pharmacology Vol. 12; p. 686874 |
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Main Authors | , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Frontiers Media S.A
06.05.2021
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Subjects | |
Online Access | Get full text |
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Summary: | Purpose:
Gastrointestinal stromal tumors (GISTs) are the most common malignant tumor of mesenchymal origin of the digestive tract. A yet more challenging resistance mechanism involves transition from oncogenic KIT to a new imatinib-insensitive oncogenic driver, heralded by loss of KIT expression. Our recent studies have shown that inhibition of cyclin D1 and Hippo signaling, which are overexpressed in KIT-independent GIST, is accompanied by anti-proliferative and apoptosis-promoting effects. PRKCQ, JUN, and the Hippo/YAP pathway coordinately regulate GIST cyclin D1 expression. Thus, targeting of these pathways could be effective therapeutically for these now untreatable tumors.
Methods:
Targeting cyclin D1 expression of small molecular drugs was screened by a cell monolayer growth and western blotting. The biologic mechanisms of bortezomib to KIT-independent GISTs were assessed by immunoblotting, qRT-PCR, cell viability, colony growth, cell cycle analysis, apoptosis, migration and invasiveness.
Results:
In the initial small molecular inhibitor screening in KIT-independent GIST62, we found that bortezomib-mediated inhibition of the ubiquitin-proteasome machinery showed anti-proliferative effects of KIT-independent GIST cells via downregulation of cyclin D1 and induction of p53 and p21. Treatment with proteasome inhibitor, bortezomib, led to downregulation of cyclin D1 and YAP/TAZ and an increase in the cleaved PARP expression in three KIT-independent GIST cell lines (GIST48B, GIST54, and GIST226). Additionally, it induced p53 and p21 expression in GIST48B and GIST54, increased apoptosis, and led to cell cycle G1/G2-phase arrest, decreased cell viability, colony formation, as well as migration and invasiveness in all GIST cell lines.
Conclusion:
Although our findings are early proof-of-principle, there are signs of a potential effective treatment for KIT-independent GISTs, the data highlight that targeting of cyclin D1 and Hippo/YAP by bortezomib warrants evaluation as a novel therapeutic strategy in KIT-independent GISTs. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Erik Berglund, Karolinska Institutet (KI), Sweden Edited by: Fanfan Zhou, The University of Sydney, Australia Reviewed by: Sergei V. Boichuk, Kazan State Medical University, Russia This article was submitted to Pharmacology of Anti-Cancer Drugs, a section of the journal Frontiers in Pharmacology These authors have contributed equally to this work and share first authorship |
ISSN: | 1663-9812 1663-9812 |
DOI: | 10.3389/fphar.2021.686874 |