Glucose deprivation activates AMPK and induces cell death through modulation of Akt in ovarian cancer cells

• Published in: Gynecologic oncology 2011-08, Vol.122 (2), p.389-395
• Main Authors: Priebe, Anna, Tan, Lijun, Wahl, Heather, Kueck, Angela, He, Gong, Kwok, Roland, Opipari, Anthony, Liu, J. Rebecca
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - metabolism; Akt; AMP-Activated Protein Kinases - physiology; AMPK; Apoptosis; Cell Line, Tumor; Deoxyglucose - pharmacology; Enzyme Activation; Female; Glucose - metabolism; Glucose Transporter Type 1 - physiology; Glycolysis; Hematology, Oncology and Palliative Medicine; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - physiology; Obstetrics and Gynecology; Ovarian cancer; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Proto-Oncogene Proteins c-akt - physiology
• ISSN: 0090-8258; 1095-6859
• DOI: 10.1016/j.ygyno.2011.04.024

Abstract Objectives Upregulation of glycolysis has been demonstrated in multiple tumor types. Glucose deprivation results in diminished intracellular ATP; this is counteracted by AMPK activation during energy deficiency to restore ATP levels. We sought to determine whether glucose deprivation could induce cytotoxicity in ovarian cancer cells through activation of AMPK, and whether AMPK activators could mimic glucose deprivation induced cytotoxicity. Methods Sensitivity to 2DG induced cytotoxicity and glucose deprivation was determined in a panel of ovarian cancer cells. Cellular growth rate, rate of glucose uptake, and response to glucose deprivation were determined. Expression of Glut-1, HIF1-α, AMPK and Akt was determined by immunoblotting. Results Incubation of ovarian cancer cells with glucose-free media, 2-DG and AMPK activators resulted in cell death. The glycolytic phenotype of ovarian cancer cells was present in both normoxic and hypoxic conditions, and did not correlate with HIF1-α expression levels. Sensitivity to glucose deprivation was independent of growth rate, rate of glucose uptake, and appeared to be dependent upon constitutive activation of Akt. Glucose deprivation resulted in activation of AMPK and inhibition of Akt phosphorylation. Treatment with AMPK activators resulted in AMPK activation, Akt inhibition, and induced cell death in ovarian cancer cells. Conclusions Ovarian cancer cells are glycolytic as compared to normal, untransformed cells, and are sensitive to glucose deprivation. Because ovarian cancer cells are dependent upon glucose for growth and survival, treatment with AMPK activators that mimic glucose deprivation may result in broad clinical benefits to ovarian cancer patients.