Genistein inhibits glucose uptake and induces autophagy in ovarian cancer cells
William Burke, Gabrielle Gossner, Angela Kueck, Milheon Choi, J. Rebecca Liu. University of Michigan Medical Ctr., Ann Arbor, MI.
Objectives: Genistein, a naturally occurring isoflavenoid abundant in soy products, has anti-neoplastic activity in multiple tumor types in vitro.
There are several mechanisms reported for genisteinís anti-neoplastic activity, including inhibition of tyrosine kinase activation, and induction of apoptosis. Constitutive activation of the tyrosine kinase Akt contributes towards inhibition of apoptosis and chemoresistance in ovarian cancer.
Activation of Akt has also been shown to enhance aerobic glycolysis in cancer cells. The purpose of this study was to determine if genistein is cytotoxic to ovarian cancer cells, and if this occurs through inhibition of Akt activation and glucose uptake.
Methods: Eight ovarian cancer cell lines were incubated with media containing glucose, genistein, or 2-deoxyglucose (2-DOG) in the presence or absence of zVAD (a generalized caspase inhibitor). Growth inhibition was determined using the sulforhodamine assay.
Viability and apoptotic fraction were determined by propidium iodide permeability and sub Go analysis respectively. Caspase and Akt activation were determined by immunoblotting. Glucose uptake was analyzed with the 3H-2-DOG assay.
Morphology was determined by light microscopy and transmission electron microscopy. Autophagic vacuoles were visualized using monodansylcadaverine staining.
Results: Genistein induced cell death in all eight ovarian cancer cell lines tested. Although genistein induced cell death in 50% of cells by 24 h, only 20% of cell death could be attributed to apoptosis as determined by PI permeability and SubGo analysis.
Moreover, genistein induced cell death in the presence or absence of zVAD. Caspase-9 activation was seen following 48 h of treatment. Genistein treatment resulted in inhibition of glucose uptake and inhibition of Akt activation by 8 hours of treatment.
Morphology was consistent with autophagic cell death.
Conclusions: Constitutive activation of Akt confers resistance to chemotherapy induced apoptosis, and enhances aerobic glycolysis in ovarian cancer cells.
We have shown that genistein inhibits Akt activation and glycolysis, and can induce both apoptotic and autophagic cell death in ovarian cancer cells. Most conventional chemotherapeutic agents induce apoptotic cell death.
Because genistein can circumvent chemoresistance due to alterations in apoptotic signaling, it has the potential to be effective against chemoresistant disease.
AACR 2005 Abstract #455
AACR 2005 Abstract #1502
AACR 2005 Abstract #4983
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