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A 3D Organotypic Melanoma Spheroid Skin Model
Published on: May 18, 2018
Identification of glycogen synthase kinase 3α as a therapeutic target in melanoma
SubbaRao V Madhunapantula1, Arati Sharma, Raghavendra Gowda
1Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, PA, USA; Penn State Melanoma Center, The Pennsylvania State University College of Medicine, Hershey, PA, USA; Penn State Melanoma Therapeutics Program, The Pennsylvania State University College of Medicine, Hershey, PA, USA.
Abstract:
Deregulated expression or activity of kinases can lead to melanomas, but often the particular kinase isoform causing the effect is not well established, making identification and validation of different isoforms regulating disease development especially important. To accomplish this objective, an siRNA screen was undertaken that which identified glycogen synthase kinase 3α (GSK3α) as an important melanoma growth regulator. Melanocytes and melanoma cell lines representing various stages of melanoma tumor progression expressed both GSK3α and GSK3β, but analysis of tumors in patients with melanoma showed elevated expression of GSK3α in 72% of samples, which was not observed for GSK3β. Furthermore, 80% of tumors in patients with melanoma expressed elevated levels of catalytically active phosphorylated GSK3α (pGSK3αY279), but not phosphorylated GSK3β (pGSK3βY216). siRNA-mediated reduction in GSK3α protein levels reduced melanoma cell survival and proliferation, sensitized cells to apoptosis-inducing agents and decreased xenografted tumor development by up to 56%. Mechanistically, inhibiting GSK3α expression using siRNA or the pharmacological agent AR-A014418 arrested melanoma cells in the G0/G1 phase of the cell cycle and induced apoptotic death to retard tumorigenesis. Therefore, GSK3α is a key therapeutic target in melanoma.
Insights
Glycogen synthase kinase 3 alpha (GSK3α) drives melanoma growth. Inhibiting GSK3α reduces tumor development and induces cancer cell death, identifying it as a key therapeutic target for melanoma.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Kinase deregulation is implicated in melanoma pathogenesis.
- Identifying specific kinase isoforms driving melanoma is crucial for targeted therapies.
Purpose of the Study:
- To identify and validate specific kinase isoforms regulating melanoma development.
- To investigate the role of glycogen synthase kinase 3 alpha (GSK3α) in melanoma.
Main Methods:
- siRNA screening to identify melanoma growth regulators.
- Expression analysis of GSK3α and GSK3β in melanoma cell lines and patient tumors.
- Assessment of catalytically active phosphorylated forms of GSK3α and GSK3β.
- Evaluation of GSK3α inhibition effects on melanoma cell survival, proliferation, apoptosis, and xenograft tumor growth.
- Cell cycle analysis and apoptosis induction studies upon GSK3α inhibition.
Main Results:
- Glycogen synthase kinase 3 alpha (GSK3α) was identified as a key regulator of melanoma growth.
- Elevated GSK3α expression and active phosphorylated GSK3α (pGSK3αY279) were observed in a majority of melanoma patient tumors.
- GSK3α inhibition via siRNA or pharmacological agents reduced melanoma cell survival, proliferation, and xenograft tumor development (up to 56%).
- GSK3α inhibition led to G0/G1 cell cycle arrest and induced apoptosis, retarding tumorigenesis.
Conclusions:
- GSK3α is significantly upregulated and plays a critical role in melanoma progression.
- Targeting GSK3α presents a promising therapeutic strategy for melanoma treatment.
- Inhibition of GSK3α effectively suppresses melanoma cell growth and induces cell death.
