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

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.