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GSK-3 as potential target for therapeutic intervention in cancer
James A McCubrey1, Linda S Steelman, Fred E Bertrand
1Department of Microbiology and Immunology,Brody School of Medicine at East Carolina University Greenville, NC 27858 USA.
Abstract:
The serine/threonine kinase glycogen synthase kinase-3 (GSK-3) was initially identified and studied in the regulation of glycogen synthesis. GSK-3 functions in a wide range of cellular processes. Aberrant activity of GSK-3 has been implicated in many human pathologies including: bipolar depression, Alzheimer's disease, Parkinson's disease, cancer, non-insulin-dependent diabetes mellitus (NIDDM) and others. In some cases, suppression of GSK-3 activity by phosphorylation by Akt and other kinases has been associated with cancer progression. In these cases, GSK-3 has tumor suppressor functions. In other cases, GSK-3 has been associated with tumor progression by stabilizing components of the beta-catenin complex. In these situations, GSK-3 has oncogenic properties. While many inhibitors to GSK-3 have been developed, their use remains controversial because of the ambiguous role of GSK-3 in cancer development. In this review, we will focus on the diverse roles that GSK-3 plays in various human cancers, in particular in solid tumors. Recently, GSK-3 has also been implicated in the generation of cancer stem cells in various cell types. We will also discuss how this pivotal kinase interacts with multiple signaling pathways such as: PI3K/PTEN/Akt/mTORC1, Ras/Raf/MEK/ERK, Wnt/beta-catenin, Hedgehog, Notch and others.
Insights
Glycogen synthase kinase-3 (GSK-3) has dual roles in cancer, acting as both a tumor suppressor and oncogene. This review explores GSK-3
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase involved in numerous cellular processes.
- Aberrant GSK-3 activity is linked to various human diseases, including cancer, neurodegenerative disorders, and diabetes.
- GSK-3's role in cancer is complex, exhibiting both tumor suppressor and oncogenic properties depending on the cellular context.
Purpose of the Study:
- To review the multifaceted roles of GSK-3 in human cancers, particularly solid tumors.
- To examine GSK-3's involvement in cancer stem cell generation.
- To elucidate GSK-3's interactions with key signaling pathways in cancer.
Main Methods:
- Literature review of studies on GSK-3 in cancer.
- Analysis of GSK-3's involvement in signaling pathways (e.g., PI3K/Akt, Wnt/beta-catenin).
- Discussion of GSK-3's role in cancer stem cell biology.
Main Results:
- GSK-3 can act as a tumor suppressor when its activity is inhibited by kinases like Akt.
- GSK-3 can promote tumor progression by stabilizing beta-catenin, indicating oncogenic properties.
- GSK-3 is implicated in the generation and maintenance of cancer stem cells.
Conclusions:
- GSK-3 plays a pivotal and context-dependent role in human cancer development.
- Understanding GSK-3's complex functions is crucial for developing effective cancer therapies.
- GSK-3's interactions with multiple signaling pathways highlight its central role in oncogenesis.
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