The Role of GSK-3[beta] in MCF-7 Breast Cancer Cell Signaling and Drug Resistance

ECU Author/Contributor (non-ECU co-authors, if there are any, appear on document)

Melissa Lynn Sokolosky (Creator)

Institution

East Carolina University (ECU )

Web Site: http://www.ecu.edu/lib/

Advisor

James A. McCubrey

Abstract: Glycogen synthase kinase- 3beta (GSK-3beta) is well documented to participate in a complex array of critical cellular processes. This versatile protein is involved in numerous signaling pathways that influence metabolism embryogenesis differentiation migration cell cycle progression and survival. Aberrant activity of GSK-3beta has been implicated in pathologies such as type-2 diabetes bipolar disorder Alzheimer's and cancer. GSK-3beta is normally active in the cytoplasm of resting cells in an unphosphorylated state where it suppresses an assortment of transcription factors implicated in oncogenesis. Lying downstream of the PI3K/PTEN/Akt pathway GSK-3beta can be negatively regulated through phosphorylation by active Akt. Given this pathway's role in malignant transformation prevention of apoptosis drug resistance and metastasis this study was performed to elucidate the role of GSK-3beta in MCF-7 breast cancer cells. It was found that cells expressing a kinase dead (KD) form of GSK-3beta were more resistant to doxorubicin and tamoxifen as well as highly clonogenic compared to cells harboring wild-type (WT) or constitutively active (A9) GSK-3beta. However when treated with rapamycin GSK-3beta KD cells show a marked decrease in proliferation as compared to WT or A9 cells. Additionally resistance to doxorubicin and tamoxifen were alleviated in KD cells upon co-treatment with the Array MEK inhibitor. Taken together these results suggest that the loss of GSK-3beta activity in MCF-7 breast cancer cells promotes clonogenicity and drug resistance but sensitizes the cells to signaling pathway blockade. Therefore targeting aberrant activity of the PI3K/PTEN/Akt/GSK-3beta pathway may be a clinically relevant tool for both increasing efficacy of and avoiding resistance to conventional therapy. 

Additional Information

Publication

Thesis

Date: 2011

Keywords

Molecular biology, Oncology, Pharmaceutical sciences, Akt, cell signaling, drug resistance, rapamycin

Subjects

Breast--Cancer--Research

Cancer--Treatment--Research

Glycogen synthase kinase-3

Protein kinases

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